Atherosclerosis 394 (2024) 117545

Contents lists available at ScienceDirect

Atherosclerosis
journal homepage: www.elsevier.com/locate/atherosclerosis

Modification of lipoprotein metabolism and function driving atherogenesis

in diabetes
Lorenzo Luciani a, b, Matteo Pedrelli a, c, Paolo Parini a, c, *
a
Cardio Metabolic Unit, Department of Laboratory Medicine, and Department of Medicine at Huddinge, Karolinska Institutet, Stockholm, Sweden
b
Interdisciplinary Center for Health Sciences, Sant’Anna School of Advanced Studies, Pisa, Italy
c
Medicine Unit of Endocrinology, Theme Inflammation and Ageing, Karolinska University Hospital, Stockholm, Sweden

A R T I C L E I N F O A B S T R A C T

Keywords: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease, characterized by raised blood glucose levels and
Lipoproteins impaired lipid metabolism resulting from insulin resistance and relative insulin deficiency. In diabetes, the
Apolipoproteins peculiar plasma lipoprotein phenotype, consisting in higher levels of apolipoprotein B-containing lipoproteins,
Atherogenesis
hypertriglyceridemia, low levels of HDL cholesterol, elevated number of small, dense LDL, and increased non-
Diabetes
Cardiometabolic disease
HDL cholesterol, results from an increased synthesis and impaired clearance of triglyceride rich lipoproteins.
Human This condition accelerates the development of the atherosclerotic cardiovascular disease (ASCVD), the most
Pre-clinical studies common cause of death in T2DM patients. Here, we review the alteration of structure, functions, and distribution
Cholesterol of circulating lipoproteins and the pathophysiological mechanisms that induce these modifications in T2DM. The
Triglycerides review analyzes the influence of diabetes-associated metabolic imbalances throughout the entire process of the
atherosclerotic plaque formation, from lipoprotein synthesis to potential plaque destabilization. Addressing the
different pathophysiological mechanisms, we suggest improved approaches for assessing the risk of adverse
cardiovascular events and clinical strategies to reduce cardiovascular risk in T2DM and cardiometabolic diseases.

1. Introduction B-containing lipoproteins, derived from both liver and gut [10,11].
These particles are consistently increased in conditions of insulin resis­
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease, tance [10] and tend to accumulate in artery walls [12], driving the
characterized by raised blood glucose levels resulting from insulin formation of plaques [13,14]. The result is about a two-fold higher
resistance and relative insulin deficiency [1,2]. According to the Inter­ frequency of fatal cardiovascular events in diabetic patients [9,15].
national Diabetes Federation’s latest report, an estimated 537 million This circumstance underscores the need for a more integrated
people globally have been diagnosed with diabetes, with T2DM ac­ approach to managing T2DM and associated pro-atherogenic dyslipi­
counting for over 90 % of these cases [3]. In addition, data suggested demia, moving beyond the traditional siloed clinical management and
that approximately another 541 million people had impaired glucose addressing it as a single, multi-faceted cardiometabolic disease [16],
tolerance in 2021 [3]. These persons share a condition of insulin resis­ which also includes the metabolic associated steatosis liver disease
tance, which is defined as the inability of insulin to exert its usual bio­ (MASLD), metabolic associated steatohepatitis (MASH), and chronic
logical functions at physiological circulating concentrations [4]. kidney disease (CKD) [17]. This review aims to examine the typical al­
Although hyperglycemia is the characteristic outcome of reduced insulin terations in the structure and distribution of circulating lipoproteins in
sensitivity, the impaired ability of insulin to regulate lipid metabolism is T2DM. It describes the pathophysiological mechanisms that induce
also responsible for the development of life-threatening diabetes com­ these modifications, exploring the influence of diabetes-associated
plications [5]. Changes in lipoprotein profile and structure [6,7] and a metabolic imbalances throughout the entire process of atherosclerotic
chronic pro-inflammatory state [8] significantly accelerate the pro­ plaque formation, from lipoprotein synthesis to potential plaque desta­
gression of atherosclerotic cardiovascular disease (ASCVD) [9]. Funda­ bilization. Finally, it reviews effective methods for assessing the risk of
mental contributors in this process are the apolipoprotein (Apo) future adverse acute events and clinical strategies to mitigate

* Corresponding author. Cardio Metabolic Unit, Department of Medicine, Karolinska Institutet, C2:94 Karolinska University Hospital Huddinge, SE-141 86,
Stockholm, Sweden.
E-mail address: [email protected] (P. Parini).

https://doi.org/10.1016/j.atherosclerosis.2024.117545
Received 6 December 2023; Received in revised form 18 March 2024; Accepted 10 April 2024
Available online 17 April 2024
0021-9150/© 2024 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
L. Luciani et al. Atherosclerosis 394 (2024) 117545

Fig. 1. Lipoprotein synthesis and clearance in diabetes.

Hyperglycemic conditions and reduced insulin sensitivity lead to an increased synthesis and secretion of triglyceride-rich lipoproteins (i.e., chylomicrons and VLDL1).
The number of circulating remnant particles is further increased by the reduced peripheral LPL activity and by decreased hepatic uptake. VLDL1 remnants are more
susceptible to the hydrolysis activity of HL, generating an elevated number of highly atherogenic and glycation-prone sdLDL. Conflicting results are nevertheless
present in humans regarding whether the CETP activity is affected in the diabetic states. ApoB-100: Apolipoprotein B-100; ApoB-48: Apolipoprotein B-48; ApoC-III:
Apolipoprotein C-III; ApoE: Apolipoprotein E; CE: Cholesteryl ester; CETP: Cholesteryl ester transfer protein; CM: Chylomicron; FFAs: Free fatty acids; glycLDL:
Glycated low-density lipoprotein; HL: Hepatic lipase; IDL: Intermediate density lipoprotein; LDLR: Low-density lipoprotein receptor; LPL: Lipoprotein lipase; MTP:
Microsomal triglyceride transfer protein; Sdc-1: Syndecan 1; sdLDL: Small, dense low-density lipoproteins; SR-B1: Scavenger receptor B1; TG: Triglycerides; VLDL:
Very-low density lipoprotein.

cardiovascular hazard in diabetic patients. has been proven to be associated with increased ASCVD risk, whether
this could be caused by modification of lipoprotein distribution has been
2. Distribution and structure of lipoproteins in type 2 diabetes accordingly investigated [19,25–27]. First, reduced levels of HDL-C
mellitus reflect a disproportion among HDL subpopulations in favour of small
and cholesterol-poor HDL, so called HDL3 [28–30]. Second, the hyper­
2.1. Alteration of lipoprotein distribution triglyceridemia consists in elevated plasma concentrations of
triglyceride-rich very low-density lipoproteins (VLDL)-1 subspecies [31,
The first approach to the diagnosis of diabetic dyslipidaemia has 32], which is associated with increased levels of chylomicrons (CM) in
historically resided in the analysis of patient’s lipid profile, which rep­ postprandial states [20,33,34]. The impaired clearance of these lipo­
resents the peripheral phenotype of patients [18–20]. Routinely, three proteins then leads to increased levels of remnant lipoprotein particles
main parameters are directly examined: triglycerides, total cholesterol, (RLP) in circulation [10], which, in contrast with previous observations,
and high-density lipoprotein-cholesterol (HDL-C), from which are currently considered even more atherogenic than LDL particles [14,
low-density lipoprotein-cholesterol (LDL-C) is calculated using the 35–37]. Further, VLDL1 remnants are susceptible to a catabolic process
widely known Friedewald’s formula or, alternatively, the more current promoting the formation of small, dense LDL (sdLDL), rather than large
Martin-Hopkins and Sampson-National Institutes of Health 2 (NIH2) and buoyant particles [38,39].
equations, which provide a more accurate estimation of LDL-C in case of As LDL-C per se does not appear to be particularly altered, there has
elevated plasma triglycerides (≥4.52 mmol/L) and low LDL-C levels been the need of novel biomarkers to better assess, and eventually
(<1.81 mmol/L) [21–23]. The typical resulting picture illustrates a explain, the increased ASCVD risk in T2DM patients [40]. With that
consistent hypertriglyceridemic state (≥1.7 mmol/L) associated with purpose, non-HDL cholesterol (non-HDL-C) and ApoB have been pro­
significantly lowered HDL-C levels (<1.03 mmol/L for men or <1.29 posed by latest ACC/AHA and ESC/EAS guidelines as improved bio­
mmol/L for women). Whilst, total cholesterol and LDL-C do not exhibit markers to assess ASCVD risk in association with traditional risk factors
considerable elevation in comparison to healthy individuals [6,19,24]. [40,41]. Non-HDL-C has been adopted in the SCORE2 algorithm as
Since the presence of this typical peripheral lipoprotein phenotype major lipid parameter for ASCVD risk assessment in general population

2
L. Luciani et al. Atherosclerosis 394 (2024) 117545

Fig. 2. Plaque progression in diabetes.

In T2DM, transcytosis of ApoB-containing lipoproteins through the endothelial barrier in arteries is increased. Once in the vascular intima, these lipoproteins show
higher affinity for proteoglycans, which lead to increased retention and structural modifications, such as oxidation and phospholipids catabolism by secretory non-
pancreatic phospholipase A2 and sphingomyelinase. These modified lipoproteins are subsequently phagocytized by macrophages, leading to the formation of foam
cells within the plaque. This entire process is amplified by the activation of RAGE receptors and the increase of FFA and ROS in the endothelial cells, thus creating a
pro-inflammatory and pro-thrombotic environment that compromises the stability of the plaque. AGE-LDL: Advanced glycation end-products low-density lipoprotein;
CCR2: CC chemokine receptor 2; CD36: Cluster of differentiation 36; EC: Endothelial cell; FFAs: Free fatty acids; glycLDL: Glycated low-density lipoprotein; ICAM-1:
Intercellular adhesion molecule 1; LP: Lipoprotein; LysoPLs: Lysophospholipids; MCP-1: Monocyte chemoattractant protein-1; NO: Nitric oxide; PAI-1: Plasminogen
activator inhibitor 1; PGs: Proteoglycans; RAGE: Receptor of advanced glycation end-products; ROS: Reactive oxygen species; sdLDL: Small, dense low-density li­
poproteins; SMC: Smooth muscle cell; SR-A: Scavenger receptor A; SR-B1: Scavenger receptor B1; tPA: Tissue plasminogen activator; VCAM-1: Vascular adhesion
molecule 1; VLDL: Very-low density lipoprotein.

[42] and, after an adjustment for age at diabetes diagnosis, HbA1c and followed by a rearrangement to a more stable ketoamine called Amadori
eGFR, it seems to be more appropriate for the prediction of ASCVD risk product (reviewed in Refs. [48,50]). Among the different lipoproteins,
also in diabetic patients (SCORE2-Diabetes) [43]. Moreover, ApoB LDL contains the highest amount of glycated ApoB (glyc-ApoB) [51,52],
stands out by exhibiting the highest positive correlation with adverse with a consistently greater susceptibility to glycation observed in sdLDL
cardiovascular events due to its better representation of the number of compared to the more buoyant LDL particles [53–55]. Hence, this sus­
circulating atherogenic particles regardless of their actual cholesterol ceptibility could explain the elevated levels of glyc-ApoB observed in
content [44,45]. This aspect is crucial in diabetic states, which are diabetic patients because of their high levels of sdLDL in circulation [56,
characterized by elevated concentrations of sdLDL (see above). Also, in 57]. Generally, LDL glycation is accompanied by some degree of
recent years LDL triglyceride (LDL-TG) is emerging as an additional oxidation, which can further increase the atherogenicity of glycated
independent marker of ASCVD in diabetic patients and its assessment particles [58]. Even in the absence of both elemental oxygen and
has been proposed as part of the future daily clinical practice [46,47]. oxygen-free radicals generated by other processes, free radicals can be
produced by glycation itself from glucose Amadori products [53,59].
2.2. Alteration of lipoprotein structure Thus, after some days in circulation, Amadori products can irreversibly
transform into highly reactive carbonyl species, known as advanced
In addition to the changes in lipoprotein distribution reported in glycation end-products (AGEs) [50,60]. AGE-LDLs have been identified
diabetes, qualitative modifications occurring in presence of insulin in atheromatous plaques of diabetic patients, showing a significant as­
resistance and/or hyperglycaemia may also contribute to increased sociation with ischemic heart disease [61,62]. However, LDL oxidation
ASCVD risk [7]. The most relevant among these structural alterations is not strictly dependent on glycation, and the two phenomena have
are glycation and oxidation. Post-secretory glycation is the most been demonstrated to be independently implicated in the pathogenesis
emblematic morphological modification affecting the conformation of of ASCVD [61,63]. Oxidative modifications in LDL enhances plaque
circulating lipoproteins in T2DM [48,49]. It consists of a non-enzymatic burden and foam cells formation. The extent of LDL oxidation in plasma
reaction, which involves the formation of a Schiff’s base between appears considerably inferior to that of glycation [64,65] and this
glucose (or one of its derived α-oxoaldehyde metabolites) and exposed discrepancy may be explained by the fact that the majority of LDL
lysine (more infrequently arginine) residues of several apolipoproteins, oxidation takes place only after penetration into the sub-endothelial

3
L. Luciani et al. Atherosclerosis 394 (2024) 117545

space, also in non-diabetic subjects [66,67]. interfering with VLDL2 levels [79,80]. This variation is primarily asso­
LDL oxidation may occur both via enzymatic and non-enzymatic ciated with the decreased anti-lipolytic action of insulin in adipose tis­
processes. The enzymatic ones involve many different pathways, some sue, both involving storage of triglycerides in the adipocytes and
of which are impaired in T2DM [7]. For instance, the myeloperoxidase suppressive effect mostly exerted on adipose triglyceride lipase (ATGL)
promotes the formation of AGEs by enhancing the reaction between [81]. Therefore, reduced suppression of lipolysis leads to augmented
apolipoprotein B-100 (ApoB-100) lysine residues and hypochlorous acid FFA flux to the liver where fatty acids undergo esterification and fuel the
[68]. Also, high glucose levels and dyslipidaemia can support lipidation of ApoB-100.
macrophage-mediated oxidation by inducing the synthesis of nicotin­ Moreover, several studies on murine models aimed to unravel the
amide adenine dinucleotide phosphate (NADPH), the main substrate of hepatic molecular mechanisms that increase VLDL1 production in con­
NADPH oxidase [69,70]. Conversely, the non-enzymatic process in­ ditions of insulin resistance (Fig. 1). Specifically, two main regulatory
volves free transition metal ions in generation of lipid peroxides and, pathways have been suggested to raise hepatic de novo lipogenesis in
subsequently, ApoB-100 protein adducts poorly recognized by LDL re­ T2DM [79,82]. First, high glucose concentrations were shown to in­
ceptor (LDLR). The drivers of this mechanism are the oxygen reactive crease in mice the expression of multiple liver lipogenic enzymes by
species, whose amount considerably increases in low level chronic in­ enforcing activation of carbohydrate response element binding protein
flammatory states like diabetes [70]. Relevant to briefly mention are (ChREBP) [83]. Second, in obese rodents, chronic compensatory
also desialylation and carbamylation, two additional modifying pro­ hyperinsulinemia led to a combined condition of insulin resistance and
cesses that participate in increasing the atherogenic potential of sdLDL sensitivity in liver. In fact, since the mechanism involving transcription
in some peculiar contexts associated with diabetic states, such as dia­ factor forkhead box O1 (FoxO1) appears to be insulin-resistant (see
betic nephropathy (reviewed in Refs. [71,72]). below), the pathway promoting lipogenesis via the induction of the
transcription factor sterol regulatory element binding protein
3. From lipoproteins synthesis to atherosclerosis in diabetic (SREBP)-1c by the mammalian target of rapamycin complex 1
patients (mTORC1) signaling complex remains sensitive to insulin [84,85].
These mechanisms may justify the increased levels of de novo lipogenesis
As described above, both lipoprotein distribution and composition detected in humans by multiple studies using different tracing meth­
are significantly altered in patients having T2DM. The major patho­ odologies [86,87]. Furthermore, the direct insulin suppression of he­
physiological manifestations of diabetes, such as insulin resistance and patic VLDL1 synthesis seems to also be impaired in diabetic rodent
hyperglycemia, are not only associated with dyslipidemic conditions models. Insulin binds to its own receptors in the hepatocyte leads to
[73], but directly determine lipoprotein alterations starting from their activation of phosphatidylinositide 3-kinase (PI3K)/Akt pathway, which
synthesis in liver or intestine (Fig. 1) until their accumulation in arterial operates the inhibition of FoxO1 by phosphorylation [88]. Inhibited
intima [74] (Fig. 2). FoxO1 does not activate the transcription of target genes, like gluco­
neogenic genes and the MTP gene, therefore reducing ApoB lipidation
3.1. Lipoprotein synthesis [88]. Also, it was demonstrated that insulin can directly affect ApoB
concentration by both decreasing ApoB translation and enhancing its
As mentioned above, a feature of diabetic dyslipidemia is hyper­ degradation in RER [89,90]. Considering that physiological inhibition of
triglyceridemia. In circulation, triglycerides are principally transported FoxO1 is reduced under conditions of insulin resistance, this molecular
by VLDL, containing ApoB-100 and secreted from the liver, and by CM, cascade is expected to determine the increase of VLDL1 plasma con­
containing apolipoprotein B-48 (ApoB-48) and are secreted from the centration. However, studies conducted on hepatic-specific Pten
intestine [75]. VLDL transport endogenous lipids from the liver to pe­ knockout mice evidenced that, even in conditions of enhanced insulin
ripheral tissues and are part of the VLDL-IDL-LDL pathway. CM trans­ sensitivity, the concomitant increase of hepatic de novo lipogenesis seems
port exogenous dietary lipids from the gut to peripheral tissues and the sufficient per se to promote ApoB secretion from the hepatocytes [91].
liver and participate to the exogenous cholesterol pathway [75]. Therefore, these data from rodent models suggest a more prominent role
VLDL assembly within the hepatocyte begins in the rough- for hepatic triglyceride accumulation within the process of VLDL1
endoplasmic reticulum (RER) where ApoB-100 is first lipidated by the secretion in insulin-resistant states. FoxO1 was also found to upregulate
microsomal transfer protein (MTP), forming a pre-VLDL. Still in the RER apolipoprotein C-III (ApoC-III) expression in the liver [92]. ApoC-III is
compartment, pre-VLDL are later converted to a small and triglyceride- an apolipoprotein mainly located on TRL surface and inhibits lipopro­
poor VLDL2 and, eventually, further lipidated to form a large and tein lipase (LPL) in peripheral tissues [75]. Moreover, ApoC-III was also
triglyceride-rich VLDL1 in the Golgi apparatus. Both VLDL1 and VLDL2 shown to be involved in VLDL1 assembly promoting the second lip­
are then secreted by liver in different proportions, with VLDL1 idation of VLDL particles in Golgi apparatus, independently from MTP
increasing in presence of large amounts of free fatty acids (FFA) and activity [93]. In diabetic states, ApoC-III gene transcription is boosted by
triglycerides [10]. In post-prandial periods hepatic VLDL secretion is several mechanisms: 1) the reduced FoxO1 inhibition [92], 2) the acti­
accompanied by CM synthesis in the gut. Non-esterified fatty acids are vation by intracellular levels of glucose of ChREBP and hepatic nuclear
absorbed from intestinal lumen by enterocytes and transported towards factor (HNF) 4α [94], and 3) by FFA stimulation of peroxisome
the RER where they encounter esterification. In the endoplasmic retic­ proliferator-activated receptor gamma coactivator 1β (PGC-1β) [95].
ulum triglycerides are subsequently associated with ApoB-48 and The resulting increase of ApoC-III secretion is therefore associated with
apolipoprotein A-IV (ApoA-IV) by MTP to form pre-CM. Pre-CM are then elevation of TRL levels, contributing to the dyslipidemic state [96].
transferred to Golgi apparatus where they are provided with apolipo­ Molecular mechanisms like those of hepatocytes provide a raising of
protein A-I (ApoA-I) and finally released as mature CM from the baso­ CM in plasma in chronic insulin-resistant subjects, both in fasting and
lateral side of the enterocyte by exocytosis [76]. postprandial states [97]. In condition of impaired insulin sensitivity, the
Physiological assembly of both triglyceride-rich lipoproteins (TRL) - increased synthesis of ApoB-48 and ApoA-IV in the enterocyte promotes
more extensively reviewed elsewhere [10,75–78] - is crucially altered in the lipidation of CM by MTP and enhances esterification and production
subjects presenting impaired insulin sensitivity. Indeed, insulin plays a of FFA, as shown by pre-clinical and clinical studies (reviewed in
key role in the control of ApoB lipoprotein metabolism by both influ­ Ref. [76]). Likewise, CM concentration might be further amplified in
encing levels of circulating substrates and the synthesis processes diabetic patients because of their leptin resistance, since studies in leptin
through complex signaling cascades in hepatocytes and enterocytes. resistant animals show a decreased secretion of glucagon-like peptide-1
Concerning VLDL metabolism, the state of insulin resistance was shown (GLP-1), a peptide hormone produced by enteroendocrine L-cells with
to enhance production and secretion of triglyceride-rich VLDL1, without several anti-diabetic roles [98]. Among these, GLP-1 was found to

4
L. Luciani et al. Atherosclerosis 394 (2024) 117545

reduce postprandial apoB-48 and triglycerides [99], therefore, impaired proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis in ro­
GLP-1 secretion could be identified as another contributing factor to CM dents. These contrasting responses are respectively generated by the
rising levels [98]. activation of transcription factor SREBP-1c [118,119] and by the inhi­
Taken together, heightened syntheses of VLDL and CM represent one bition of HNF1α and HNF4α, two transcriptional factors controlled by
of the main contributors to diabetic dyslipidemia, paving the way to the mTORC complex [120]. In humans, elevated plasma levels of PCSK9
subsequent atherosclerotic complications. in T2DM are reported by several epidemiological studies [121–123], but
other works attempting to reproduce hyperinsulinemic conditions have
3.2. Clearance in plasma not shown any alteration in circulating PCSK9 levels [124]. Therefore,
whether or not plasma PCSK9 levels are impaired by insulin resistance in
Dysregulation of plasma clearance of ApoB-containing lipoproteins is diabetic patients remains a controversial issue.
another driving factor of diabetic dyslipidemia (Fig. 1). Normally, the Several studies in mice have highlighted that when LDLR is
secreted VLDL and CM triglycerides are hydrolyzed by LPL in the cap­ dysfunctional the internalization of ApoE-containing lipoproteins can
illaries of the peripheral tissues. This metabolic process leads to the also be supplied by other receptors located on the surface of hepatocytes,
formation of RLP, smaller particles containing ApoB, ApoE, free and such as LDL receptor-related protein 1 (LRP1), another member of LDLR
esterified cholesterol and a greatly reduced amount of triglycerides. family [75,88], or syndecan-1 (Sdc-1), a heparan sulfate proteoglycan
Starting from this point, the fate of VLDL remnants, also known as in­ [101]. However, their supporting role seems to be less relevant in
termediate density lipoproteins (IDL), and CM remnants is partly insulin-resistant states since their synthesis and expression in the liver is
different. CM remnants are rapidly cleared from plasma by ApoE- drastically reduced [125–128]. This evidence might suggest some sup­
recognizing receptors on the surface of hepatocytes, such as LDLR, plementary mechanisms contributing to the increase of RLP in diabetes,
LDL receptor-related protein 1 (LRP1) and syndecan-1 (Sdc-1). On the but data showing similar processes in human are still lacking and
other hand, IDL only partially undergo rapid endocytosis in the liver, deserve additional research in the future.
whereas the remaining fraction undergoes further metabolism mainly Besides the alteration of receptor functionality, the impairment of
via hepatic lipase (HL). The result of this process is formation of RLP clearance is also linked to structural changes affecting circulating
cholesterol-rich LDL, which persists in circulation for 2–3 days before lipoproteins in diabetic patients. In the last years, an increased under­
being eliminated via endocytosis by LDLR [75,88,100,101]. standing of the pathophysiological role of ApoC-III in triglyceride-rich
In T2DM, both the plasma hydrolysis and the hepatic uptake of RLP lipoprotein clearance has been gained. If the role of ApoC-III in
appear to be imbalanced, subsequently determining a reduced fractional reducing the hepatic uptake of RLP has been postulated for decades
clearance of LDL which results to be reversible after insulin adminis­ [129], the underlying mechanisms have only recently been hypothe­
tration [102,103]. sized. Studies in mice using antisense oligonucleotides aimed to reduce
Regarding the first metabolic process, it has been hypothesized that ApoC-III revealed that this apolipoprotein inhibits the ApoE-mediated
impaired insulin sensitivity determines reduced expression and activity uptake of lipoproteins, impairing the LDLR/LRP1 axis, without
of LPL leading to lower hydrolysis of triglycerides [104–106]. The affecting the Sdc-1 binding activity [130]. ApoC-III seems to provoke
reduced hydrolysis was originally believed to result only from an conformational changes in ApoE masking some binding domains and
increased synthesis of ApoC-III, which is a non-competitive inhibitor of preventing efficient binding to, e.g., the LDLR [131]. Yet, these confor­
LPL [75,107]. Lately, other mechanisms involving the angiopoietin-like mation changes are not affecting the ApoE sites involved in Sdc-1
proteins (ANGPTL) 3, 4 and 8 have been also found to influence LPL binding [131]. However, two recent studies in humans with APOC3
activity [108]. Physiologically, circulating ANGPTL proteins promote loss-of-function mutations showed a higher rate of conversion of VLDL
the unfolding of the hydrolase domain in LPL, resulting in the dissoci­ to LDL generated by a greater lipolytic activity of LPL, which is not
ation of LPL dimers into LPL monomers [109]. This mechanism leads to accompanied by an increased direct removal of RLP in the liver [132,
the inhibition of LPL activity in both the fed and fasted state. In the fed 133]. Whether direct hepatic uptake of RLP is relevant for the clearance
state, ANGPTL3/ANGPTL8 complexes promote the replenishment of of ApoB-containing lipoproteins currently remains controversial.
adipocytes while concurrently inhibiting the uptake of circulating tri­ In light of these considerations, it is easier to understand why LDL
glycerides into peripheral tissues [110]. Conversely, ANGPTL4 prevents metabolism also appears to be profoundly altered in T2DM. As discussed
the uptake of plasma triglycerides into tissues during fasting [110]. previously, diabetic patients show an increase in number of circulating
Several in vitro and in vivo studies highlighted the crucial role of insulin sdLDL (also known as subclass B). The process leading to increased
in modulating ANGPTL proteins synthesis and secretion by liver and sdLDL formation is primarily associated with higher plasma concentra­
adipose tissue [111,112]. Specifically, exposure to hyperinsulinemic tions of triglyceride-rich VLDL1 [134,135].
conditions consistently reduces ANGPTL3 and ANGPTL4 levels, while By exchanging triglycerides in ApoB-containing lipoproteins for
ANGPTL8 levels increase [113,114]. These findings in healthy subjects cholesteryl ester in HDL, CETP decreases the triglycerides content and
align with results from other clinical studies, in which in individuals increases the cholesterol cargo of VLDL and LDL particles [136]. Con­
with diabetes or insulin resistance ANGPTL proteins, particularly of flicting results are nevertheless present in humans regarding whether
ANGPTL3, behaved in an opposite manner [115]. These insights clear the CETP activity is affected in the diabetic states. If a study from France
the way for further exploration of pathways of therapeutic interest that shows a decreased CETP mass paralleled by an increased CETP activity
may impact TRL catabolism in diabetes. [137], another study from Hong Kong found the opposite in both sexes
The uptake of RLP from the blood mainly involves three types of [138]. Whether these conflicting observations are due to differences in
receptors in liver: the LDLR, also known as the ApoB/ApoE receptor, the genetic background of the diabetic patients studied is unfortunately
LPR1 and some types of heparan sulfate proteoglycans (HSPGs). In impossible to rule out. Since the triglyceride-rich LDL resulting from the
diabetic states, both insulin resistance and hyperglycemia have been partial peripheral catabolism of VLDL1 have reduced affinity for LDLR
described to impair their physiological functions through different [139], their longer residence time in circulation makes them more sus­
mechanisms. By binding ApoB and ApoE, LDLR greatly contribute to ceptible to the action of HL. This enzyme further decreases their tri­
RLP uptake. Studies in human HepG2 cells suggest that Ldlr gene glyceride content and leads to the production of a large number of sdLDL
expression may be reduced by insulin resistance [116]. This hypothesis particles [140]. Independently of the substrate availability, i.e., number
has been further corroborated by a study in monocyte cells of poorly of triglyceride-rich LDL in circulation, this process is further enhanced
controlled diabetic patients, whose LDLR surface expression was by an increased activity of HL itself [138]. sdLDL are characterized by a
reduced and thereafter normalized upon insulin treatment [117]. sub-optimal triglycerides/core cholesteryl-ester ratio impairing the
Moreover, insulin has been shown to both promote and inhibit molecular organization and the structural conformation of the

5
L. Luciani et al. Atherosclerosis 394 (2024) 117545

ApoB-100 binding site domain and reducing the affinity of these small of a disulfide bridge between two cysteines and makes the positively
and dense lipoproteins for LDLR. These changes in ApoB-100 are one of charged amino acids (lysines and arginines) located in the proteoglycan
the key factors leading to longer plasma half-life of the sdLDL [139]. binding site (the so called “site B″, ammino acid residues 3359 to 3369)
Increased glycemia and longer sdLDL half-life in turn promote closer to each other [163,164]. The resulting increase in charge density
non-enzymatic glycation of ApoB-100 to such an extent that is poorly strengthens the binding to negatively charged glycosaminoglycans
recognized by LDLR [141,142]. This further increases sdLDL number in chains on PGs [159,163,165].
circulation, worsening the pro-atherogenic condition of diabetic pa­ In addition to sdLDL, smaller TRL and their remnants, which are
tients. Also, lipoprotein(a) (Lp(a)) is subjected to glycation, and in vivo markedly increased in diabetic patients, can also cross the endothelial
studies have shown that the percentage of glycated Lp(a) in diabetic surface, and avidly bind to PGs [145,166–168]. In addition to ApoB-100,
patients is significantly higher than in the control population [143]. both ApoB-48 and ApoE contain proteoglycan-binding domains [169,
Nevertheless, the observation that Lp(a) is less susceptible to glycation 170]. Hence, broader spectrum of lipoproteins accumulates in the vessel
than LDL, it has been speculated that glycation of LDL may be more wall where they take part in the atherosclerosis development, and not
relevant to the cardiovascular risk associated with this particle than with exclusively sdLDL [150,167]. In particular, the intimal retention of CM
Lp(a) [143]. It is also interesting to mention that in 8411 individuals remnants, which contain ApoB-48, was found to be approximately
from the Copenhagen City Heart Study, a high number of KIV-2 repeats two-fold higher than that observed for LDL [150,168]. For this reason
in Lp(a) are associated causally with increased risk of type 2 diabetes, and also taking into account the greater amount of lipids carried by CM
and not the low Lp(a) concentrations per se [144]. remnants, these particles largely contribute to the vascular lipid depo­
sition [151,153,171]. In diabetes, lipoprotein accumulation is further
3.3. Trans-endothelial migration and retention in the artery wall enhanced by reduced levels in the intima of large HDL2, which normally
competes with formation of irreversible LDL-PGs aggregates by estab­
The lipoprotein modifications that occur in diabetes strongly influ­ lishing reversible bonds with PGs themselves [172]. It is more debated
ence also the mechanisms involved in their influx, and consequent whether glycLDL and ApoC-III rich lipoproteins have an enhanced li­
retention, in the arterial intima (Fig. 2). The endothelial surface of ar­ poprotein retention in diabetes. Glycation should be expected to reduce
teries can be crossed by lipoproteins of up to about 70–100 nm in the binding affinity to PGs due to the decrease of the number of positive
diameter [145–147]. Newer evidence from studies on two endothelial charges on the surfaces of lipoproteins through the formation of lysine
receptors, the so-called scavenger receptor (SR)-B1 and activin-like ki­ adducts [48]. However, some studies, aiming to highlight the binding
nase 1 (ALK1), suggests that also even very large particle, and likely affinity of glycLDL and their aldehyde derivatives (e.g.,
even CM, may cross endothelial surface after undergoing lipolysis once methylglyoxal-LDL) to proteoglycans, have instead shown an increased
bound to those receptors [147,148]. Although the molecular mechanism retention of these lipoproteins in the intimal EM [173,174]. The
regulating lipoprotein transport into vessel walls needs to be fully explanation of this unexpected results is that only selected lysines are
elucidated, several studies in recent years have demonstrated that LDL is affected by glycation, and that the overall effect on the LDL particle is to
able to cross the endothelial barrier through a process of transcytosis concentrate positive charges on the particle surface, generating an ApoB
(reviewed in Ref. [149]). The majority of the crossing particles efflux on with a higher propensity to bind PGs [174].
the adventitial side [150], with a limited amount of them being retained Considering that increased ApoC-III content in ApoB-containing li­
intravascularly through electrostatic binding to proteoglycans (PGs) of poproteins is a strong cardiovascular risk factors [175], these ApoC-III
the extracellular matrix (EM) [12,151]. Here, lipoproteins can undergo enriched lipoproteins were expected to exhibit an increased proathero­
conformational and structural modifications (e.g., oxidation), increasing genic potential in patients with T2DM by also presenting a higher af­
their atherogenic properties [12,152]. The magnitude of these modifi­ finity for PGs. However, if in first studies ApoC-III enriched VLDL, IDL,
cations is markedly influenced by several different risk factors [153], and LDL showed a significantly increased binding to biglycans [176],
among which diabetes plays a pivotal role. this evidence acquired smaller relevance in following analyses [177].
Despite the limited number of studies on this topic, some mecha­ Further, this property disappeared when lipoproteins were enriched by
nisms demonstrate that LDL transcytosis may be enhanced after their exogenous ApoC-III in vitro [176]. These contrasting features are
modifications in diabetic patients. Under physiological conditions, LDL explained by the fact that ApoC-III cannot bind PGs directly, but it can
particles have been shown to bind to SR-B1 and ALK1, located in cav­ instead affect ApoB accessibility to biglycans by inducing conforma­
eolae on the luminal side of the endothelial cell [147–149]. Once bound, tional changes [176,177]. It has been proposed that in diabetic patients
LDL are internalized and transported to the sub endothelial space side elevated levels of ApoC-III may uncover an additional binding site on
where they are released [154]. In T2DM, circulating AGEs, potentially ApoB-100 lipoproteins (site A) by altering the lipoprotein surface sec­
including AGE-LDL, can accelerate LDL transcytosis by binding to the ondary to modification of phospholipid distribution [177]. However,
receptor for advanced glycated end products (RAGE), which activates a very high levels of ApoC-III in LDL were found to reduce the binding of
molecular cascade inducing the expression of caveolin-1, the key protein these particles to biglycans, due to further changes in ApoB-100
in LDL internalization [155]. Furthermore, glycated LDL (glycLDL) are configuration [177].
found to cross the endothelial layer more rapidly than native LDL thanks It should be finally noted that not only lipoprotein alterations lead to
to the recognition of a specific type of scavenger receptor, the SR-A an increase in their retention in vessel walls. Indeed, also the pro­
[156]. Also, in diabetes lipoprotein efflux from the vessel into intercel­ teoglycans and other macromolecules in the EM undergo qualitative and
lular space appears to be consistently reduced, to the point that the quantitative modifications that enhance their tendency to bind to
number of ApoB-containing lipoproteins detected in the interstitial fluid atherogenic particles, thus contributing to initiating the atherosclerotic
of diabetic patients is significantly lower compared to controls [157], process in diabetic states (see more in Refs. [159,178]).
even if vessel permeability in diabetes is notoriously enhanced [158],
suggesting a greater susceptibility of these lipoproteins to be retained in 3.4. Plaque formation
the arterial wall. In this line, sdLDL particles isolated from T2DM pa­
tients display increased PGs binding within the arterial intima [151, Once bound to proteoglycans, the ApoB-containing lipoproteins
159–161]. undergo additional modifications, making retention one of the primary
In sdLDL, the reduced phospholipid content induces a 50 % increase mechanisms for the onset of atherosclerosis [12,179]. The immobiliza­
in lipoprotein core surface area requiring a greater coverage by ApoB- tion of atherogenic particles in the intima increases the exposure of the
100, which results in a 56 % decrease in protein thickness [162]. This surface monolayer phospholipids to hydrolysis by secretory
additional conformational change of ApoB-100 facilitates the formation non-pancreatic phospholipase A2 (sPLA2). This enzyme co-localizes

6
L. Luciani et al. Atherosclerosis 394 (2024) 117545

with lipoproteins in the EM by binding to similar PGs [180,181]. This cells is not sufficient to wholly sustain generations of macrophages in the
process results in an increased concentration of FFA and lysophospho­ plaque and it is helped by the phenotypic switching of smooth muscle
lipids within the intimal extracellular space [182,183]. These products cells (SMC) and by an additional recruitment [216] of monocytes from
have been shown to intensify inflammation [184,185] and cell prolif­ the circulation [215]. Two major subtypes of macrophages detected
eration [186,187], and thus contributing to atherogenesis [13]. within the atheroma can be distinguished by their surface expression of
The higher levels of ApoC-III on lipoproteins surface can promote the CD14 and CD16 [217]. CD14++CD16− monocytes represent the typical
activity of sphingomyelinase, another lipase located in the EM [177, pro-inflammatory subspecies, whilst CD14+CD16++ monocytes have
188]. This enzyme can convert LDL sphingomyelins into ceramides been recognized as non-classical, patrolling cells with an atheropro­
which are potent pro-inflammatory and pro-aggregating lipid signals tective potential role induced by the bond between ox-LDL and CD36
[189,190]. Interestingly, sphingomyelin itself is known to inhibit the [218]. Since several pro-inflammatory mechanisms trigger the recruit­
activity of at least two isoforms of sPLA2 [191]. Therefore, the decreased ment of these monocytes within the arterial wall even in non-diabetic
content of sphingomyelin creates a proatherogenic condition indepen­ subjects [13], the elevated concentrations of both glycLDL and
dently of ceramides by promoting the enzymatic modification of remnant particles can consistently upregulate the synthesis of chemo­
ApoB-containing particles [177]. However, it is believed that the most tactic factors and the exposure of adhesion molecules on the surface of
prominent consequence of the subendothelial retention of endothelial cells (EC) in diabetic persons [219,220]. Circulating glycLDL
ApoB-containing particles resides in the increased sensitivity of sdLDL to have been shown to bind to RAGE receptors located on the luminal side
oxidative reactions [152]. Several studies demonstrated that the inter­ of EC [221]. When stimulated, this receptor induces a wide range of
action with proteoglycans of sdLDL increased their susceptibility to signaling events, including the activation of NF-κB and p38 MAP kinase,
oxidation by facilitating the access of Cu2+ cations to internal hydro­ which are two transcription factors involved in the expression of
phobic regions [192,193]. Additionally, the prolonged permanence in vascular cell adhesion molecule 1 (VCAM-1) and CC chemokine receptor
the EM provides the required time for an extensive free radical-mediated 2 (CCR2) [222,223]. The first protein is directly responsible for the
oxidative modification of retained sdLDL [194] that appears to be initial attachment and rolling over of leukocytes [224], while the latter
further increased by eventual previous glycation of the particles [193]. is deputed to recognize and bind the monocyte chemoattractant
These alterations, along with products of enzymatic oxidation (see also protein-1 (MCP-1), a pro-inflammatory chemokine whose release in
above), represent a primary driver for the creation of an atherosclerotic plasma is in turn increased after the exposure to high levels of AGE-LDL
microenvironment [12,194]. [225]. Stimulation of RAGE also promotes the production of reactive
The key role played by oxidized and glycoxidated LDL particles in the oxygen species (ROS) through the activation of NADPH oxidase tran­
development of the atherosclerotic plaque has been extensively docu­ scription and the suppression of the expression of mitochondrial elec­
mented and includes both the genesis of macrophage-derived foam cells tron transport chain complexes [79,226]. This dual action compromises
and the establishment of a chronic inflammatory milieu, thereby the functional integrity of endothelial subcellular structures, especially
participating in plaque enlargement and necrotic core formation [13, mitochondria and endoplasmic reticulum [219,226], therefore leading
195–198]. The two types of modified LDL contribute to the development to a further expansion of cellular stress [219] and to an increase in the
of lipid-laden foam cells within the plaque by activating identical cas­ number of RAGE molecules on the endothelial surface [225], thereby
cades [199]. The uptake of modified LDL by macrophages occurs mainly amplifying a self-powering pro-inflammatory environment.
through three scavenger receptors: SR-A, CD36, and LOX-1 [195, Furthermore, in diabetic dyslipidemia, the oxidative stress origi­
200–202]. Their expression may be upregulated both by the activity of nating from the accumulation of FFA in the EC derived from lipolysis of
inflammatory cytokines and by the modified LDL particle itself, through TRL potentiates chemotaxis of monocytes [227]. Neutral and oxidized
a harmful feed-forward mechanism based on the activation of gran­ FFA provoke pro-inflammatory responses by increasing TNFα secretion,
ulocyte/macrophage colony stimulating factor (GM-CSF) and peroxi­ intracellular adhesion molecule 1 (ICAM-1) expression, and ROS pro­
some proliferator-activated receptor gamma (PPARγ) [203–206]. Also, duction through the activation of NADPH oxidase and cytochrome
the exposure of macrophages to elevated glucose levels was demon­ P450-mediated mechanisms [227]. Moreover, TRL can contribute to
strated to further increase the expression of scavenger receptors [207]. creating a proatherogenic environment by directly inducing other
In association with the mechanism mentioned above, the accumu­ different pathways. For instance, IDL was found to stimulate MCP-1
lation of cholesterol inside plaque macrophages is significantly accel­ mRNA transcription in EC [228], while ApoC-III rich VLDL can pro­
erated by the internalization of small TRL and their remnants mote the expression of VCAM-1 and ICAM-1 by activating protein kinase
[208–210]. These particles are characterized by a 2.5-fold higher C β and NF-κB signaling cascades [229]. In addition, recent studies have
cholesterol mass, i.e., number of molecules, compared to LDL, trans­ indicated that elevated rates of circulating TRL remnants provide a
ferring thus greater amount of cholesterol per particle into the plaque considerable increase in the accumulation of lipids within monocytes,
[14,211]. Despite fewer in number than LDL within the arterial wall even before their penetration in the vascular wall [230,231]. It is
[168], they acquire a relevant role in the progression of the plaque interesting to notice that in mice models a consistent part of these foamy
because, contrarily to native LDL, they can recognize multiple macro­ monocytes belongs to the lymphocyte antigen 6 complex locus C low
phage receptors also through ApoE and/or ApoB-48 [210,212], without (Ly6Clo) group, which corresponds to non-classical monocytes in
necessarily undergoing oxidative alterations [213]. Nevertheless, humans [232]. Considering that high levels of lipid-laden Ly6Clo
oxidation of remnants can sometimes occur in vessels, further increasing monocytes have been shown to participate to early atherosclerosis
their atherogenic potential [213]. [230], it is plausible that their atheroprotective patrolling activity is also
From this point on, macrophage uptake of lipoproteins enhances impaired, although this hypothesis needs to be further explored [231].
maturation to a pro-inflammatory phenotype, although ongoing studies The metabolic environment of T2DM can affect the HDL structure
are questioning this hypothesis [214], favors formation of cholesterol and function, therefore reducing its anti-inflammatory and antioxidant
monohydrate crystals, promotes the activation of cell apoptosis, and properties [233] and dampening the reverse cholesterol transport from
ultimately exerts defective efferocytotic activity increasing the devel­ lipid-laden macrophages [234,235]. Specifically, the glycation of the
opment of a necrotic core in the atherosclerotic plaque (reviewed in HDL-associated protein paroxonase-1 impairs its ability to counterbal­
Ref. [13]). ance myeloperoxidase oxidative activity on LDL, thus enhancing
Originally, vascular dendritic cells were thought to initiate athero­ oxLDL-induced MCP-1 formation by EC [236]. Moreover, oxidative
sclerosis by being the first to accumulate cholesterol, but recent studies damage of ApoA-I reduces its affinity to the ATP-binding cassette A1
on mice requalified the myeloid cells in the intima as the origin of (ABCA1) and ATP-binding cassette G1 (ABCG1), consequently
specific resident macrophages [215]. However, the proliferation of these decreasing cholesterol efflux from foam cells and promoting the

7
L. Luciani et al. Atherosclerosis 394 (2024) 117545

exposure on plaque macrophages surface of Toll-like receptor-2/4, a percentiles [44,45,253–256]. Hence, an effective therapeutic strategy
pro-inflammatory chemokines inducer (reviewed in Ref. [234]). for diabetes and cardiometabolic disease at large, should focus on
reducing the number of circulating ApoB-containing lipoproteins by
3.5. Plaque destabilization targeting the molecular mechanisms responsible for their impairment
[257]. This notion also relies on the results from two recent trials that
The influence exerted by modified lipoproteins on plaque progres­ aimed to reduce the residual cardiovascular risk in patients with T2DM
sion and instability still deserves to be thoroughly explored. However, a by reducing triglycerides levels in bloodstream [258,259]. In the
logical consequence of the accelerated foamy cells apoptosis is the rapid PROMINENT trial was employed pemafibrate, a new selective PPARα
expansion of plaque necrotic core [231], which is a typical feature of agonist [258], while the concomitant REDUCE-IT trial was conducted by
lesions at high risk of rupturing with consequent thrombus formation using icosapent ethyl (IPE), a highly purified and stable eicosapentae­
[13]. The development of necrotic core generally stimulates local SMC noic acid ethyl ester [259]. Both the interventions achieved statistically
to proliferate and subsequently migrate to subendothelial space, where significant reductions of triglycerides after four months of treatment
they change their phenotype to fibroblast-like cell in order to create a (respectively − 26.8 % and − 21.3 %) and similar values were main­
layer of proteoglycans and hyaluronan, called fibrous cap, that prevents tained until the last visits (after 41 and 59 months in average, respec­
the plaque from breaking [216]. In the early stage of T2DM, glycated tively) [258,259]. Only IPE showed a significantly 25 % lower risk of
and slightly oxidized LDL have been observed to enhance SMC migra­ cardiovascular events compared to placebo, whilst pemafibrate sur­
tion, but when higher levels of glycoxidation are achieved a significant prisingly presented no clinical benefit [258,259]. The divergent clini­
cell injury and apoptosis has been observed [237]. These observations, cally relevant outcomes might be explained by the different effects on
associated with the increased uptake of cholesterol-rich lipoproteins ApoB levels, which were but slightly increased in PROMINENT, whereas
[211], underscore the role of SMC in the enlargement of necrotic core in significantly decreased in REDUCE-IT, when the median between-group
advanced stage of atherosclerosis. Moreover, significant data suggest a difference (i.e., the difference between placebo and icosapent ethyl
role for AGEs in promoting calcification of SMC [238], although the group) was considered [258,259]. If a reduction of ApoB is a prerequi­
potential contribution of AGE-LDL to this process currently remains a site for positively affect cardiovascular outcomes, the N-acetyl
hypothesis. galactosamine-conjugated antisense oligonucleotide targeting APOCIII
If larger necrotic cores [239] and enhanced calcification [238] in­ gene in liver (olezarsen, formerly known as AKCEA-APOCIII-LR), seems
crease the risk of plaque disruption in diabetic patients with thin-cap to be a very attractive new compound to target the dyslipidemia char­
fibroatheroma [240], the subsequent thrombotic event is further acteristic of the cardiometabolic disease, including diabetes. A phase 2
amplified by the interaction of glycated and oxidized lipoproteins with clinical trial conducted on 114 patients with elevated fasting serum
endothelial receptors [241,242]. Specifically, the activation of RAGE triglycerides (2.26–5.65 mmol/L) evidenced that olezarsen not only
signaling cascade, coupled with a greater concentration of ROS in induces the expected decrease in ApoC-III (− 74 %), triglycerides (− 60
cytoplasm (see above), has been shown to create a pro-thrombotic %), and non-HDL-C (− 19 %) at the highest tested dosage, but also a
environment by influencing the production of a set of anti- and significant decrease in ApoB levels (− 10 %) [260]. Recently, similar
pro-aggregating molecules, such as nitric oxide and tissue plasminogen positive effects on the lipid profile have been achieved by silencing the
activator, which are reduced [242–245], and plasminogen activating APOCIII gene through a double-stranded small interfering RNA, known
inhibitor-1, whose synthesis is instead augmented [241,244–246]. The as ARO-APOCIII [261]. In the same line of reasoning, other promising
effects exerted by glycLDL on platelet functionality are noteworthy treatments may be the inhibitors of ANGPTL3 [257]. Specifically, evi­
[247]. The deeply altered surface charges of glycLDL is thought to drive nacumab, a monoclonal antibody employed in severe familial hyper­
a defective rearrangement of the platelet plasma membrane transport cholesterolemia, has demonstrated high effectiveness in reducing
enzyme Na+/K+-ATPase [248]. As a consequence, the inhibition of the triglycerides, non-HDL-C and ApoB in hypertriglyceridemic subjects in
sodium pump determines an increase in Na+/Ca2+ exchange, which in two separate phase 1 clinical trials, each characterized by a different
turn raises cytosolic calcium concentrations [247] leading to platelet administration schedule [262]. In addition, ARO-APOC3, an RNA
activation [249]. interfering therapy that targets ANGPTL3, seems to improve all the lipid
parameters both in health subjects and patients affected by hepatic
4. Clinical management of CARDIO metabolic disease steatosis. This suggests that it could potentially be a useful tool for
ASCVD prevention soon [263]. A further interesting therapeutic option
The detailed understanding of the modifications of lipoprotein may be saroglitazar, a PPARα/γ agonist, that in phase III clinical trials
metabolism and functions in diabetes accentuates the importance of a exhibited significant improvement both in glycemic control and dysli­
holistic approach in managing patients with diabetes and car­ pidemia by decreasing not only triglycerides and non-HDL-C, but also
diometabolic disease. Although the correlation between diabetes and ApoB [264,265]. Interestingly, this drug did not illustrate the short-term
pro-atherogenic dyslipidemia has been known for decades [250], the side effects of other thiazolidinediones [266], underscoring its real po­
two conditions were frequently treated separately [16,251], in line with tential in treating cardiometabolic disease.
a specialty-based and organ-driven view of medicine. Thus, the goal was Also, GLP-1 receptor agonists are molecules of great interest for
to maintain glucose and LDL-C levels below their respective treatment reducing the cardiovascular risk since they affect dyslipidemias by
goals to prevent the onset of disease-related complications [16,251]. decreasing the postprandial synthesis of ApoB-48 and triglycerides in
Despite the presence of adequate control of LDL-C levels, the presence of CM, as well as the secretion of VLDL [267].
a residual ASCVD shows the complexity of atherogenesis in diabetes
[252], which is comprehensible after the in-depth analysis of diverse 5. Conclusions
pathophysiological mechanisms driving dyslipidemia and atherogen­
esis. Hence, it is no surprising that the increased tendency to develop Patients with T2DM are characterized by a significantly increased
unstable atherosclerotic plaques is not exclusively attributable to LDL-C atherosclerosis cardiovascular risk compared to non-diabetic patients.
accumulation in vessels. The substantial increase in circulating RLP and This is largely due to their peculiar lipid profile, consisting in higher
the structural modifications of all the pro-atherogenic particles signifi­ levels of ApoB-containing particles, hypertriglyceridemia, low levels of
cantly contribute to this threatening process as well. These observations HDL-C, elevated number of small, dense LDL, and increased non-HDL-C,
are keys to understanding those clinical trials identifying ApoB as a all resulting from increased synthesis and impaired clearance of
better predictor of cardiovascular risk than LDL-C and non-HDL-C, triglyceride-rich lipoproteins secondary to reduced insulin sensitivity,
especially in those individuals who present triglycerides at the highest and which create the conditions for cholesterol to become a highly pro-

8
L. Luciani et al. Atherosclerosis 394 (2024) 117545

Fig. 3. Graphical abstract.

Patients with type 2 diabetes face an increased atherosclerosis cardiovascular risk due to higher circulating levels of Apolipoprotein B (ApoB)-containing particles,
especially small, dense low-density lipoproteins, and increased lipoproteins glycation, all resulting from impaired synthesis and clearance of triglyceride-rich li­
poproteins secondary to reduced insulin sensitivity. These ApoB-containing lipoproteins readily cross the endothelial barrier via transcytosis and are highly retained
in vessel walls. Resident macrophages then take them up, initiating an inflammatory process that progressively contributes to plaque expansion and adverse car­
diovascular events.

atherogenic and pro-inflammatory molecule (Fig. 3). Indeed, therapies [5] P. Meerarani, et al., Metabolic syndrome and diabetic atherothrombosis:
implications in vascular complications, Curr. Mol. Med. 6 (5) (2006) 501–514.
aimed at lowering cholesterol currently stand as the cornerstone for
[6] A. Pirillo, et al., Global epidemiology of dyslipidaemias, Nat. Rev. Cardiol. 18
atherosclerosis prevention, particularly in diabetic patients. Raised (10) (2021) 689–700.
plasma glucose concentrations are responsible for major structural li­ [7] I. Bonilha, et al., The Reciprocal relationship between LDL metabolism and type 2
poprotein modifications observed in T2DM and several studies shows diabetes mellitus, Metabolites 11 (12) (2021).
[8] T.V. Rohm, et al., Inflammation in obesity, diabetes, and related disorders,
these modified ApoB-containing lipoproteins to have a marked tendency Immunity 55 (1) (2022) 31–55.
to be retained in vessel walls and to be readily taken up by resident [9] N.D. Wong, N. Sattar, Cardiovascular risk in diabetes mellitus: epidemiology,
macrophages. Furthermore, this process can be amplified by a pro- assessment and prevention, Nat. Rev. Cardiol. 20 (10) (2023) 685–695.
[10] B. Vergès, Abnormal hepatic apolipoprotein B metabolism in type 2 diabetes,
inflammatory state, facilitated by the interaction of modified lipopro­ Atherosclerosis 211 (2) (2010) 353–360.
teins with the endothelial surface. In summary, these mechanisms [11] J. Cole, et al., Use of apolipoprotein B in the Era of Precision medicine: time for a
accelerate the expansion of atherosclerotic lesions, thereby increasing Paradigm change? J. Clin. Med. 12 (17) (2023).
[12] K.J. Williams, I. Tabas, The response-to-retention hypothesis of early
the risk of adverse cardiovascular events for diabetic patients. Inference atherogenesis, Arterioscler. Thromb. Vasc. Biol. 15 (5) (1995) 551–561.
of clinical intervention studies identify the number of ApoB-containing [13] J. Borén, et al., Low-density lipoproteins cause atherosclerotic cardiovascular
lipoproteins as a stronger driver of the pathological processes resulting disease: pathophysiological, genetic, and therapeutic insights: a consensus
statement from the European Atherosclerosis Society Consensus Panel, Eur. Heart
in clinical outcomes than their composition in triglycerides and J. 41 (24) (2020) 2313–2330.
cholesterol. This emphasizes the need to evaluate levels of circulating [14] H.N. Ginsberg, et al., Triglyceride-rich lipoproteins and their remnants: metabolic
ApoB, in association to LDL-C and non-HDL-C, as marker of cardiovas­ insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic
strategies-a consensus statement from the European Atherosclerosis Society, Eur.
cular risk in diabetic patients not only in tertiary care settings.
Heart J. 42 (47) (2021) 4791–4806.
[15] N. Sarwar, et al., Diabetes mellitus, fasting blood glucose concentration, and risk
Financial support of vascular disease: a collaborative meta-analysis of 102 prospective studies,
Lancet 375 (9733) (2010) 2215–2222.
[16] S. Jacob, et al., Evolution of type 2 diabetes management from a Glucocentric
This work was supported by grants from Karolinska Institutet, Re­ approach to Cardio-Renal risk reduction: the new Paradigm of care, Drugs 81 (12)
gion Stockholm, Sant’Anna School of Advanced Studies – Pisa, and (2021) 1373–1379.
European Union under Repo4EU grant No. 101057619. [17] D.R. Saxon, et al., Cardiometabolic medicine: development of a new Subspecialty,
J. Clin. Endocrinol. Metab. 105 (7) (2020).
[18] E.R. Briones, et al., Analysis of plasma lipids and apolipoproteins in insulin-
Declaration of competing interest dependent and noninsulin-dependent diabetics, Metabolism 33 (1) (1984) 42–49.
[19] M. Eriksson, et al., Blood lipids in 75,048 type 2 diabetic patients: a population-
based survey from the Swedish National diabetes register, Eur. J. Cardiovasc.
The authors declare that they have no known competing financial Prev. Rehabil. 18 (1) (2011) 97–105.
interests or personal relationships that could have appeared to influence [20] V. Higgins, K. Adeli, Postprandial dyslipidemia in insulin resistant states in
adolescent populations, J Biomed Res 34 (5) (2020) 328–342.
the work reported in this paper. [21] W.T. Friedewald, R.I. Levy, D.S. Fredrickson, Estimation of the concentration of
low-density lipoprotein cholesterol in plasma, without use of the preparative
References ultracentrifuge, Clin. Chem. 18 (6) (1972) 499–502.
[22] S.S. Martin, et al., Comparison of a novel method vs the Friedewald equation for
estimating low-density lipoprotein cholesterol levels from the standard lipid
[1] M.M. Alberti, K. G, P. Zimmet, Classification and diagnosis of diabetes mellitus,
profile, JAMA 310 (19) (2013) 2061–2068.
in: J.A.H. Wass, et al. (Eds.), Oxford Textbook of Endocrinology and Diabetes,
[23] M. Sampson, et al., A new equation for calculation of low-density lipoprotein
Oxford University Press, 2011.
cholesterol in patients with Normolipidemia and/or hypertriglyceridemia, JAMA
[2] U. Galicia-Garcia, et al., Pathophysiology of type 2 diabetes mellitus, Int. J. Mol.
Cardiol 5 (5) (2020) 540–548.
Sci. 21 (17) (2020).
[24] R. Scott, et al., Impact of metabolic syndrome and its components on
[3] D.J. Magliano, E.J. Boyko, I.D.F.D.A.T.E.S. Committee, IDF diabetes Atlas, in: Idf
cardiovascular disease event rates in 4900 patients with type 2 diabetes assigned
Diabetes Atlas, International Diabetes Federation © International Diabetes
to placebo in the FIELD randomised trial, Cardiovasc. Diabetol. 10 (2011) 102.
Federation, Brussels, 2021, 2021.
[25] A.D. Kaze, et al., Metabolic dyslipidemia and cardiovascular outcomes in type 2
[4] H. Yki-Järvinen, Pathophysiology of type 2 diabetes mellitus, in: J.A.H. Wass, et
diabetes mellitus: findings from the Look AHEAD study, J. Am. Heart Assoc. 10
al. (Eds.), Oxford Textbook of Endocrinology and Diabetes, Oxford University
(7) (2021) e016947.
Press, 2011.

9
L. Luciani et al. Atherosclerosis 394 (2024) 117545

[26] M.J. Chapman, et al., Triglyceride-rich lipoproteins and high-density lipoprotein [57] N. Younis, et al., Glycation as an atherogenic modification of LDL, Curr. Opin.
cholesterol in patients at high risk of cardiovascular disease: evidence and Lipidol. 19 (4) (2008) 378–384.
guidance for management, Eur. Heart J. 32 (11) (2011) 1345–1361. [58] K. Kobayashi, et al., Glycation accelerates the oxidation of low density lipoprotein
[27] H. Sone, et al., Serum level of triglycerides is a potent risk factor comparable to by copper ions, Endocr. J. 42 (4) (1995) 461–465.
LDL cholesterol for coronary heart disease in Japanese patients with type 2 [59] A.J. Jenkins, et al., Lipoproteins, glycoxidation and diabetic angiopathy, Diabetes
diabetes: subanalysis of the Japan Diabetes Complications Study (JDCS), J. Clin. Metab Res Rev 20 (5) (2004) 349–368.
Endocrinol. Metab. 96 (11) (2011) 3448–3456. [60] S. Ahmad, et al., Glycoxidation of biological macromolecules: a critical approach
[28] W.S. Davidson, A.S. Shah, High-density lipoprotein subspecies in health and to halt the menace of glycation, Glycobiology 24 (11) (2014) 979–990.
human disease: focus on type 2 diabetes, Methodist Debakey Cardiovasc J 15 (1) [61] Y. Imanaga, et al., In vivo and in vitro evidence for the glycoxidation of low
(2019) 55–61. density lipoprotein in human atherosclerotic plaques, Atherosclerosis 150 (2)
[29] W.S. Davidson, et al., Obesity is associated with an altered HDL subspecies profile (2000) 343–355.
among adolescents with metabolic disease, J. Lipid Res. 58 (9) (2017) [62] A.A. K, S. Muniandy, S.I. I, Role of N-(carboxymethyl)lysine in the development
1916–1923. of ischemic heart disease in type 2 diabetes mellitus, J. Clin. Biochem. Nutr. 41
[30] P. Piko, et al., Association of HDL subfraction profile with the progression of (2) (2007) 97–105.
insulin resistance, Int. J. Mol. Sci. 24 (17) (2023). [63] D. Li, et al., Effect of alpha-tocopherol on LDL oxidation and glycation: in vitro
[31] M. Adiels, et al., Overproduction of very low-density lipoproteins is the hallmark and in vivo studies, J. Lipid Res. 37 (9) (1996) 1978–1986.
of the dyslipidemia in the metabolic syndrome, Arterioscler. Thromb. Vasc. Biol. [64] M.P. Cohen, Y. Jin, G.T. Lautenslager, Increased plasma glycated low-density
28 (7) (2008) 1225–1236. lipoprotein concentrations in diabetes: a marker of atherogenic risk, Diabetes
[32] R. Malmström, et al., Defective regulation of triglyceride metabolism by insulin in Technol. Therapeut. 6 (3) (2004) 348–356.
the liver in NIDDM, Diabetologia 40 (4) (1997) 454–462. [65] J. Banerjee, et al., Beyond LDL-c: the importance of serum oxidized LDL in
[33] S. Lim, et al., Postprandial dyslipidemia after a standardized high-fat meal in BMI- predicting risk for type 2 diabetes in the middle-aged Asian Indians, Diabetes
matched healthy individuals, and in subjects with prediabetes or type 2 diabetes, Metabol. Syndr. 13 (1) (2019) 206–213.
Clin. Nutr. 40 (11) (2021) 5538–5546. [66] M. Meuwissen, et al., Colocalisation of intraplaque C reactive protein,
[34] G. Annuzzi, et al., Postprandial chylomicrons and adipose tissue lipoprotein lipase complement, oxidised low density lipoprotein, and macrophages in stable and
are altered in type 2 diabetes independently of obesity and whole-body insulin unstable angina and acute myocardial infarction, J. Clin. Pathol. 59 (2) (2006)
resistance, Nutr. Metabol. Cardiovasc. Dis. 18 (8) (2008) 531–538. 196–201.
[35] B.N. Wadström, et al., Elevated remnant cholesterol and atherosclerotic [67] A. Hartley, D. Haskard, R. Khamis, Oxidized LDL and anti-oxidized LDL
cardiovascular disease in diabetes: a population-based prospective cohort study, antibodies in atherosclerosis - novel insights and future directions in diagnosis
Diabetologia (2023). and therapy<sup, Trends Cardiovasc. Med. 29 (1) (2019) 22–26.
[36] E. Björnson, et al., Triglyceride-rich lipoprotein remnants, low-density [68] L.J. Hazell, J.J. van den Berg, R. Stocker, Oxidation of low-density lipoprotein by
lipoproteins, and risk of coronary heart disease: a UK Biobank study, Eur. Heart J. hypochlorite causes aggregation that is mediated by modification of lysine
44 (39) (2023) 4186–4195. residues rather than lipid oxidation, Biochem. J. 302 (Pt 1) (1994) 297–304. Pt 1.
[37] A. Helgadottir, et al., Cholesterol not particle concentration mediates the [69] M. Aviram, et al., Activation of NADPH oxidase required for macrophage-
atherogenic risk conferred by apolipoprotein B particles: a Mendelian mediated oxidation of low-density lipoprotein, Metabolism 45 (9) (1996)
randomization analysis, Eur J Prev Cardiol 29 (18) (2022) 2374–2385. 1069–1079.
[38] S. Kathiresan, et al., Increased small low-density lipoprotein particle number: a [70] M.A. Darenskaya, L.I. Kolesnikova, S.I. Kolesnikov, Oxidative stress: Pathogenetic
prominent feature of the metabolic syndrome in the Framingham Heart Study, role in diabetes mellitus and its complications and therapeutic approaches to
Circulation 113 (1) (2006) 20–29. Correction, Bull. Exp. Biol. Med. 171 (2) (2021) 179–189.
[39] S. Maeda, et al., Associations between small dense LDL, HDL subfractions (HDL2, [71] V.I. Summerhill, et al., The atherogenic role of circulating modified lipids in
HDL3) and risk of atherosclerosis in Japanese-Americans, J. Atherosclerosis atherosclerosis, Int. J. Mol. Sci. 20 (14) (2019).
Thromb. 19 (5) (2012) 444–452. [72] D. Denimal, Carbamylated lipoproteins in diabetes, World J. Diabetes 14 (3)
[40] F. Mach, et al., 2019 ESC/EAS Guidelines for the management of dyslipidaemias: (2023) 159–169.
lipid modification to reduce cardiovascular risk, Eur. Heart J. 41 (1) (2020) [73] S.M. Haffner, et al., Insulin sensitivity in subjects with type 2 diabetes.
111–188. Relationship to cardiovascular risk factors: the Insulin Resistance Atherosclerosis
[41] D.K. Arnett, et al., 2019 ACC/AHA guideline on the primary prevention of Study, Diabetes Care 22 (4) (1999) 562–568.
cardiovascular disease: a report of the American College of Cardiology/American [74] G.M. Reaven, M.S. Greenfield, Diabetic hypertriglyceridemia: evidence for three
heart association Task Force on clinical practice guidelines, Circulation 140 (11) clinical syndromes, Diabetes 30 (Suppl 2) (1981) 66–75.
(2019) e596–e646. [75] B. Angelin, P. Parini, Lipoprotein metabolism, in: Oxford Textbook of
[42] SCORE2 risk prediction algorithms: new models to estimate 10-year risk of Endocrinology and Diabetes, 2011, pp. 1659–1667.
cardiovascular disease in Europe, Eur. Heart J. 42 (25) (2021) 2439–2454. [76] B. Vergès, Intestinal lipid absorption and transport in type 2 diabetes,
[43] SCORE2-Diabetes, 10-year cardiovascular risk estimation in type 2 diabetes in Diabetologia 65 (10) (2022) 1587–1600.
Europe, Eur. Heart J. 44 (28) (2023) 2544–2556. [77] S. Tiwari, S.A. Siddiqi, Intracellular trafficking and secretion of VLDL,
[44] M.J. Pencina, et al., Apolipoprotein B improves risk assessment of future coronary Arterioscler. Thromb. Vasc. Biol. 32 (5) (2012) 1079–1086.
heart disease in the Framingham Heart Study beyond LDL-C and non-HDL-C, Eur [78] A. Giammanco, et al., The pathophysiology of intestinal lipoprotein production,
J Prev Cardiol 22 (10) (2015) 1321–1327. Front. Physiol. 6 (2015) 61.
[45] C.D.L. Johannesen, et al., Apolipoprotein B and non-HDL cholesterol better reflect [79] M. Adiels, et al., Overproduction of VLDL1 driven by hyperglycemia is a
residual risk than LDL cholesterol in statin-treated patients, J. Am. Coll. Cardiol. dominant feature of diabetic dyslipidemia, Arterioscler. Thromb. Vasc. Biol. 25
77 (11) (2021) 1439–1450. (8) (2005) 1697–1703.
[46] !!! INVALID CITATION !!! {Silbernagel, 2019 #17;Silbernagel, 2019 #17}. [80] R.F. Johansen, et al., Basal and insulin-regulated VLDL1 and VLDL2 kinetics in
[47] J.L. Jin, et al., Long-term prognostic utility of low-density lipoprotein (LDL) men with type 2 diabetes, Diabetologia 59 (4) (2016) 833–843.
triglyceride in real-world patients with coronary artery disease and diabetes or [81] T.S. Nielsen, et al., Dissecting adipose tissue lipolysis: molecular regulation and
prediabetes, Cardiovasc. Diabetol. 19 (1) (2020) 152. implications for metabolic disease, J. Mol. Endocrinol. 52 (3) (2014) R199–R222.
[48] H. Soran, P.N. Durrington, Susceptibility of LDL and its subfractions to glycation, [82] J.M. Schwarz, et al., Hepatic de novo lipogenesis in normoinsulinemic and
Curr. Opin. Lipidol. 22 (4) (2011) 254–261. hyperinsulinemic subjects consuming high-fat, low-carbohydrate and low-fat,
[49] L.K. Curtiss, J.L. Witztum, A.I. Plasma apolipoproteins, AII, B, CI, and E are high-carbohydrate isoenergetic diets, Am. J. Clin. Nutr. 77 (1) (2003) 43–50.
glucosylated in hyperglycemic diabetic subjects, Diabetes 34 (5) (1985) 452–461. [83] S. Ishii, et al., Carbohydrate response element binding protein directly promotes
[50] A.V. Poznyak, et al., Glycation of LDL: AGEs, impact on lipoprotein function, and lipogenic enzyme gene transcription, Proc. Natl. Acad. Sci. U.S.A. 101 (44) (2004)
involvement in atherosclerosis, Front Cardiovasc Med 10 (2023) 1094188. 15597–15602.
[51] F.J. Tames, et al., Non-enzymatic glycation of apolipoprotein B in the sera of [84] I. Shimomura, et al., Decreased IRS-2 and increased SREBP-1c lead to mixed
diabetic and non-diabetic subjects, Atherosclerosis 93 (3) (1992) 237–244. insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice, Mol.
[52] M.P. Cohen, G. Lautenslager, E. Shea, Glycated LDL concentrations in non- Cell 6 (1) (2000) 77–86.
diabetic and diabetic subjects measured with monoclonal antibodies reactive [85] L. Khamzina, et al., Increased activation of the mammalian target of rapamycin
with glycated apolipoprotein B epitopes, Eur. J. Clin. Chem. Clin. Biochem. 31 pathway in liver and skeletal muscle of obese rats: possible involvement in
(11) (1993) 707–713. obesity-linked insulin resistance, Endocrinology 146 (3) (2005) 1473–1481.
[53] N. Younis, et al., Glycation of LDL in non-diabetic people: small dense LDL is [86] A. Vedala, et al., Delayed secretory pathway contributions to VLDL-triglycerides
preferentially glycated both in vivo and in vitro, Atherosclerosis 202 (1) (2009) from plasma NEFA, diet, and de novo lipogenesis in humans, J. Lipid Res. 47 (11)
162–168. (2006) 2562–2574.
[54] N.N. Younis, et al., Small-dense LDL and LDL glycation in metabolic syndrome [87] G.I. Smith, et al., Insulin resistance drives hepatic de novo lipogenesis in
and in statin-treated and non-statin-treated type 2 diabetes, Diabetes Vasc. Dis. nonalcoholic fatty liver disease, J. Clin. Invest. 130 (3) (2020) 1453–1460.
Res. 7 (4) (2010) 289–295. [88] M.E. Haas, A.D. Attie, S.B. Biddinger, The regulation of ApoB metabolism by
[55] N.N. Younis, et al., Small dense LDL is more susceptible to glycation than more insulin, Trends Endocrinol. Metabol. 24 (8) (2013) 391–397.
buoyant LDL in Type 2 diabetes, Clin. Sci. (Lond.) 124 (5) (2013) 343–349. [89] K.G. Sidiropoulos, et al., Insulin inhibition of apolipoprotein B mRNA translation
[56] S.R. Kashyap, et al., Glycation reduces the stability of ApoAI and increases HDL is mediated via the PI-3 kinase/mTOR signaling cascade but does not involve
dysfunction in diet-controlled type 2 diabetes, J. Clin. Endocrinol. Metab. 103 (2) internal ribosomal entry site (IRES) initiation, Arch. Biochem. Biophys. 465 (2)
(2018) 388–396. (2007) 380–388.

10
L. Luciani et al. Atherosclerosis 394 (2024) 117545

[90] C. Taghibiglou, et al., Hepatic very low density lipoprotein-ApoB overproduction [122] Y. Nekaies, et al., Plasma proprotein convertase subtilisin/kexin type 9 is
is associated with attenuated hepatic insulin signaling and overexpression of associated with Lp(a) in type 2 diabetic patients, J. Diabet. Complicat. 29 (8)
protein-tyrosine phosphatase 1B in a fructose-fed hamster model of insulin (2015) 1165–1170.
resistance, J. Biol. Chem. 277 (1) (2002) 793–803. [123] D. Ibarretxe, et al., Circulating PCSK9 in patients with type 2 diabetes and related
[91] B.C. Moon, et al., Apolipoprotein B secretion is regulated by hepatic triglyceride, metabolic disorders, Clín. Invest. Arterioscler. 28 (2) (2016) 71–78.
and not insulin, in a model of increased hepatic insulin signaling, Arterioscler. [124] P.J. Kappelle, G. Lambert, R.P. Dullaart, Plasma proprotein convertase subtilisin-
Thromb. Vasc. Biol. 32 (2) (2012) 236–246. kexin type 9 does not change during 24h insulin infusion in healthy subjects and
[92] J. Altomonte, et al., Foxo1 mediates insulin action on apoC-III and triglyceride type 2 diabetic patients, Atherosclerosis 214 (2) (2011) 432–435.
metabolism, J. Clin. Invest. 114 (10) (2004) 1493–1503. [125] A. Laatsch, et al., Insulin stimulates hepatic low density lipoprotein receptor-
[93] M. Sundaram, et al., Expression of apolipoprotein C-III in McA-RH7777 cells related protein 1 (LRP1) to increase postprandial lipoprotein clearance,
enhances VLDL assembly and secretion under lipid-rich conditions, J. Lipid Res. Atherosclerosis 204 (1) (2009) 105–111.
51 (1) (2010) 150–161. [126] T. Ebara, et al., Delayed catabolism of apoB-48 lipoproteins due to decreased
[94] S. Caron, et al., Transcriptional activation of apolipoprotein CIII expression by heparan sulfate proteoglycan production in diabetic mice, J. Clin. Invest. 105 (12)
glucose may contribute to diabetic dyslipidemia, Arterioscler. Thromb. Vasc. Biol. (2000) 1807–1818.
31 (3) (2011) 513–519. [127] K. Chen, et al., Type 2 diabetes in mice induces hepatic overexpression of
[95] C. Hernandez, et al., Regulation of hepatic ApoC3 expression by PGC-1β mediates sulfatase 2, a novel factor that suppresses uptake of remnant lipoproteins,
hypolipidemic effect of nicotinic acid, Cell Metabol. 12 (4) (2010) 411–419. Hepatology 52 (6) (2010) 1957–1967.
[96] M. Adiels, et al., Role of apolipoprotein C-III overproduction in diabetic [128] H.C. Hassing, et al., SULF2 strongly prediposes to fasting and postprandial
dyslipidaemia, Diabetes Obes. Metabol. 21 (8) (2019) 1861–1870. triglycerides in patients with obesity and type 2 diabetes mellitus, Obesity 22 (5)
[97] M. Haidari, et al., Fasting and postprandial overproduction of intestinally derived (2014) 1309–1316.
lipoproteins in an animal model of insulin resistance. Evidence that chronic [129] E. Windler, R.J. Havel, Inhibitory effects of C apolipoproteins from rats and
fructose feeding in the hamster is accompanied by enhanced intestinal de novo humans on the uptake of triglyceride-rich lipoproteins and their remnants by the
lipogenesis and ApoB48-containing lipoprotein overproduction, J. Biol. Chem. perfused rat liver, J. Lipid Res. 26 (5) (1985) 556–565.
277 (35) (2002) 31646–31655. [130] P.L. Gordts, et al., ApoC-III inhibits clearance of triglyceride-rich lipoproteins
[98] P. Stahel, et al., Role of the gut in diabetic dyslipidemia, Front. Endocrinol. 11 through LDL family receptors, J. Clin. Invest. 126 (8) (2016) 2855–2866.
(2020) 116. [131] B. Ramms, et al., ApoC-III ASO promotes tissue LPL activity in the absence of
[99] C. Xiao, et al., Exenatide, a glucagon-like peptide-1 receptor agonist, acutely apoE-mediated TRL clearance, J. Lipid Res. 60 (8) (2019) 1379–1395.
inhibits intestinal lipoprotein production in healthy humans, Arterioscler. [132] G. Reyes-Soffer, et al., Effects of APOC3 Heterozygous deficiency on plasma lipid
Thromb. Vasc. Biol. 32 (6) (2012) 1513–1519. and lipoprotein metabolism, Arterioscler. Thromb. Vasc. Biol. 39 (1) (2019)
[100] B. Vergès, New insight into the pathophysiology of lipid abnormalities in type 2 63–72.
diabetes, Diabetes Metab. 31 (5) (2005) 429–439. [133] M.R. Taskinen, et al., Postprandial metabolism of apolipoproteins B48, B100, C-
[101] A.D. Cooper, Hepatic uptake of chylomicron remnants, J. Lipid Res. 38 (11) III, and E in humans with APOC3 loss-of-function mutations, JCI Insight 7 (19)
(1997) 2173–2192. (2022).
[102] A.H. Kissebah, et al., Plasma low density lipoprotein transport kinetics in [134] A.M. Georgieva, et al., Subclasses of low-density lipoprotein and very low-density
noninsulin-dependent diabetes mellitus, J. Clin. Invest. 71 (3) (1983) 655–667. lipoprotein in familial combined hyperlipidemia: relationship to multiple
[103] L. Duvillard, et al., Significant improvement of apolipoprotein B-containing lipoprotein phenotype, Arterioscler. Thromb. Vasc. Biol. 24 (4) (2004) 744–749.
lipoprotein metabolism by insulin treatment in patients with non-insulin- [135] M.R. Taskinen, J. Borén, New insights into the pathophysiology of dyslipidemia in
dependent diabetes mellitus, Diabetologia 43 (1) (2000) 27–35. type 2 diabetes, Atherosclerosis 239 (2) (2015) 483–495.
[104] S.K. Fried, et al., Lipoprotein lipase regulation by insulin and glucocorticoid in [136] G.J. de Grooth, et al., A review of CETP and its relation to atherosclerosis, J. Lipid
subcutaneous and omental adipose tissues of obese women and men, J. Clin. Res. 45 (11) (2004) 1967–1974.
Invest. 92 (5) (1993) 2191–2198. [137] B. Bouillet, et al., Glycation of apolipoprotein C1 impairs its CETP inhibitory
[105] C.N. Sadur, R.H. Eckel, Insulin stimulation of adipose tissue lipoprotein lipase. property: pathophysiological relevance in patients with type 1 and type 2
Use of the euglycemic clamp technique, J. Clin. Invest. 69 (5) (1982) 1119–1125. diabetes, Diabetes Care 37 (4) (2014) 1148–1156.
[106] O. Adeyo, et al., Glycosylphosphatidylinositol-anchored high-density lipoprotein- [138] K.C. Tan, S.W. Shiu, B.Y. Chu, Roles of hepatic lipase and cholesteryl ester
binding protein 1 and the intravascular processing of triglyceride-rich transfer protein in determining low density lipoprotein subfraction distribution in
lipoproteins, J. Intern. Med. 272 (6) (2012) 528–540. Chinese patients with non-insulin-dependent diabetes mellitus, Atherosclerosis
[107] W.V. Brown, M.L. Baginsky, Inhibition of lipoprotein lipase by an apoprotein of 145 (2) (1999) 273–278.
human very low density lipoprotein, Biochem. Biophys. Res. Commun. 46 (2) [139] F. Nigon, et al., Discrete subspecies of human low density lipoproteins are
(1972) 375–382. heterogeneous in their interaction with the cellular LDL receptor, J. Lipid Res. 32
[108] W. Dijk, S. Kersten, Regulation of lipid metabolism by angiopoietin-like proteins, (11) (1991) 1741–1753.
Curr. Opin. Lipidol. 27 (3) (2016) 249–256. [140] B. Vergès, Lipid modification in type 2 diabetes: the role of LDL and HDL,
[109] E.C. Lee, et al., Identification of a new functional domain in angiopoietin-like 3 Fundam. Clin. Pharmacol. 23 (6) (2009) 681–685.
(ANGPTL3) and angiopoietin-like 4 (ANGPTL4) involved in binding and [141] X. Wang, R. Bucala, R. Milne, Epitopes close to the apolipoprotein B low density
inhibition of lipoprotein lipase (LPL), J. Biol. Chem. 284 (20) (2009) lipoprotein receptor-binding site are modified by advanced glycation end
13735–13745. products, Proc. Natl. Acad. Sci. U.S.A. 95 (13) (1998) 7643–7647.
[110] S. Kersten, New insights into angiopoietin-like proteins in lipid metabolism and [142] J.L. Witztum, et al., Nonenzymatic glucosylation of low-density lipoprotein alters
cardiovascular disease risk, Curr. Opin. Lipidol. 30 (3) (2019) 205–211. its biologic activity, Diabetes 31 (4 Pt 1) (1982) 283–291.
[111] M. Shimamura, et al., Leptin and insulin down-regulate angiopoietin-like protein [143] C. Doucet, et al., Non-enzymatic glycation of lipoprotein(a) in vitro and in vivo,
3, a plasma triglyceride-increasing factor, Biochem. Biophys. Res. Commun. 322 Atherosclerosis 118 (1) (1995) 135–143.
(3) (2004) 1080–1085. [144] A. Tolbus, et al., Kringle IV type 2, not low lipoprotein(a), as a cause of diabetes: a
[112] P.A. Nidhina Haridas, et al., Regulation of angiopoietin-like proteins (ANGPTLs) 3 novel genetic approach using SNPs associated selectively with lipoprotein(a)
and 8 by insulin, J. Clin. Endocrinol. Metab. 100 (10) (2015) E1299–E1307. concentrations or with Kringle IV type 2 repeats, Clin. Chem. 63 (12) (2017)
[113] D.H. van Raalte, et al., Angiopoietin-like protein 4 is differentially regulated by 1866–1876.
glucocorticoids and insulin in vitro and in vivo in healthy humans, Exp. Clin. [145] B.G. Nordestgaard, R. Wootton, B. Lewis, Selective retention of VLDL, IDL, and
Endocrinol. Diabetes 120 (10) (2012) 598–603. LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo. Molecular
[114] M. Abu-Farha, et al., Plasma insulin is required for the increase in plasma size as a determinant of fractional loss from the intima-inner media, Arterioscler.
angiopoietin-like protein 8 in response to nutrient ingestion, Diabetes Metab Res Thromb. Vasc. Biol. 15 (4) (1995) 534–542.
Rev 39 (6) (2023) e3643. [146] B.G. Nordestgaard, D.B. Zilversmit, Large lipoproteins are excluded from the
[115] Y. Yilmaz, et al., Serum concentrations of human angiopoietin-like protein 3 in arterial wall in diabetic cholesterol-fed rabbits, J. Lipid Res. 29 (11) (1988)
patients with nonalcoholic fatty liver disease: association with insulin resistance, 1491–1500.
Eur. J. Gastroenterol. Hepatol. 21 (11) (2009) 1247–1251. [147] S.M. Armstrong, et al., A novel assay uncovers an unexpected role for SR-BI in
[116] D.P. Wade, B.L. Knight, A.K. Soutar, Regulation of low-density-lipoprotein- LDL transcytosis, Cardiovasc. Res. 108 (2) (2015) 268–277.
receptor mRNA by insulin in human hepatoma Hep G2 cells, Eur. J. Biochem. 181 [148] J.R. Kraehling, et al., Genome-wide RNAi screen reveals ALK1 mediates LDL
(3) (1989) 727–731. uptake and transcytosis in endothelial cells, Nat. Commun. 7 (2016) 13516.
[117] L. Duvillard, et al., Cell surface expression of LDL receptor is decreased in type 2 [149] T.W.W. Ho, A. Henry, W.L. Lee, LDL transcytosis by the arterial endothelium-
diabetic patients and is normalized by insulin therapy, Diabetes Care 26 (5) atherosclerosis by a Thousand Cuts? Curr. Atherosclerosis Rep. 25 (8) (2023)
(2003) 1540–1544. 457–465.
[118] P. Costet, et al., Hepatic PCSK9 expression is regulated by nutritional status via [150] S.D. Proctor, J.C. Mamo, Intimal retention of cholesterol derived from
insulin and sterol regulatory element-binding protein 1c, J. Biol. Chem. 281 (10) apolipoprotein B100- and apolipoprotein B48-containing lipoproteins in carotid
(2006) 6211–6218. arteries of Watanabe heritable hyperlipidemic rabbits, Arterioscler. Thromb.
[119] M. Niesen, M. Bedi, D. Lopez, Diabetes alters LDL receptor and PCSK9 expression Vasc. Biol. 23 (9) (2003) 1595–1600.
in rat liver, Arch. Biochem. Biophys. 470 (2) (2008) 111–115. [151] P. Fogelstrand, J. Borén, Retention of atherogenic lipoproteins in the artery wall
[120] D. Ai, et al., Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice, and its role in atherogenesis, Nutr. Metabol. Cardiovasc. Dis. 22 (1) (2012) 1–7.
J. Clin. Invest. 122 (4) (2012) 1262–1270. [152] E. Hurt-Camejo, et al., Effect of arterial proteoglycans and glycosaminoglycans on
[121] S.G. Lakoski, et al., Genetic and metabolic determinants of plasma PCSK9 levels, low density lipoprotein oxidation and its uptake by human macrophages and
J. Clin. Endocrinol. Metab. 94 (7) (2009) 2537–2543. arterial smooth muscle cells, Arterioscler. Thromb. 12 (5) (1992) 569–583.

11
L. Luciani et al. Atherosclerosis 394 (2024) 117545

[153] L.R. Tannock, V.L. King, Proteoglycan mediated lipoprotein retention: a [183] G. Camejo, Lysophospholipids: effectors mediating the contribution of
mechanism of diabetic atherosclerosis, Rev. Endocr. Metab. Disord. 9 (4) (2008) dyslipidemia to calcification associated with atherosclerosis, Atherosclerosis 211
289–300. (1) (2010) 36–37.
[154] E. Vasile, M. Simionescu, N. Simionescu, Visualization of the binding, [184] A.A. Murphy, et al., Lysophosphatidyl choline, a chemotactic factor for
endocytosis, and transcytosis of low-density lipoprotein in the arterial monocytes/T-lymphocytes is elevated in endometriosis, J. Clin. Endocrinol.
endothelium in situ, J. Cell Biol. 96 (6) (1983) 1677–1689. Metab. 83 (6) (1998) 2110–2113.
[155] M. Shu, et al., AGEs promote atherosclerosis by increasing LDL transcytosis across [185] T. Murohara, R. Scalia, A.M. Lefer, Lysophosphatidylcholine promotes P-selectin
endothelial cells via RAGE/NF-κB/Caveolin-1 pathway, Mol. Med. 29 (1) (2023) expression in platelets and endothelial cells. Possible involvement of protein
113. kinase C activation and its inhibition by nitric oxide donors, Circ. Res. 78 (5)
[156] W. Cheng, et al., Scavenger receptor a mediates glycated LDL transcytosis across (1996) 780–789.
endothelial cells to promote atherosclerosis, Int. J. Biol. Macromol. 235 (2023) [186] N. Kume, M.A. Gimbrone Jr., Lysophosphatidylcholine transcriptionally induces
123836. growth factor gene expression in cultured human endothelial cells, J. Clin. Invest.
[157] J. Apro, et al., Levels of atherogenic lipoproteins are unexpectedly reduced in 93 (2) (1994) 907–911.
interstitial fluid from type 2 diabetes patients, J. Lipid Res. 56 (8) (2015) [187] Y.C. Chai, et al., Oxidized low density lipoprotein and lysophosphatidylcholine
1633–1639. stimulate cell cycle entry in vascular smooth muscle cells. Evidence for release of
[158] G.C. Viberti, Increased capillary permeability in diabetes mellitus and its fibroblast growth factor-2, J. Biol. Chem. 271 (30) (1996) 17791–17797.
relationship to microvascular angiopathy, Am. J. Med. 75 (5b) (1983) 81–84. [188] S.L. Schissel, et al., Secretory sphingomyelinase, a product of the acid
[159] G. Camejo, et al., The extracellular matrix on atherogenesis and diabetes- sphingomyelinase gene, can hydrolyze atherogenic lipoproteins at neutral pH.
associated vascular disease, Atherosclerosis Suppl. 3 (1) (2002) 3–9. Implications for atherosclerotic lesion development, J. Biol. Chem. 273 (5) (1998)
[160] V. Anber, et al., Influence of plasma lipid and LDL-subfraction profile on the 2738–2746.
interaction between low density lipoprotein with human arterial wall [189] S.L. Schissel, et al., Rabbit aorta and human atherosclerotic lesions hydrolyze the
proteoglycans, Atherosclerosis 124 (2) (1996) 261–271. sphingomyelin of retained low-density lipoprotein. Proposed role for arterial-wall
[161] E. Hurt-Camejo, et al., Differential uptake of proteoglycan-selected subfractions of sphingomyelinase in subendothelial retention and aggregation of atherogenic
low density lipoprotein by human macrophages, J. Lipid Res. 31 (8) (1990) lipoproteins, J. Clin. Invest. 98 (6) (1996) 1455–1464.
1387–1398. [190] K. Oörni, et al., Sphingomyelinase induces aggregation and fusion, but
[162] J.R. McNamara, et al., Differences in LDL subspecies involve alterations in lipid phospholipase A2 only aggregation, of low density lipoprotein (LDL) particles.
composition and conformational changes in apolipoprotein B, J. Lipid Res. 37 (9) Two distinct mechanisms leading to increased binding strength of LDL to human
(1996) 1924–1935. aortic proteoglycans, J. Biol. Chem. 273 (44) (1998) 29127–29134.
[163] L. Chan, B. Apolipoprotein, The major protein component of triglyceride-rich and [191] L. Gesquiere, W. Cho, P.V. Subbaiah, Role of group IIa and group V secretory
low density lipoproteins, J. Biol. Chem. 267 (36) (1992) 25621–25624. phospholipases A(2) in the metabolism of lipoproteins. Substrate specificities of
[164] U. Olsson, et al., Possible functional interactions of apolipoprotein B-100 the enzymes and the regulation of their activities by sphingomyelin, Biochemistry
segments that associate with cell proteoglycans and the ApoB/E receptor, 41 (15) (2002) 4911–4920.
Arterioscler. Thromb. Vasc. Biol. 17 (1) (1997) 149–155. [192] G. Camejo, et al., Modification of copper-catalyzed oxidation of low density
[165] J. Borén, et al., Identification of the principal proteoglycan-binding site in LDL. A lipoprotein by proteoglycans and glycosaminoglycans, J. Lipid Res. 32 (12)
single-point mutation in apo-B100 severely affects proteoglycan interaction (1991) 1983–1991.
without affecting LDL receptor binding, J. Clin. Invest. 101 (12) (1998) [193] A. Ravandi, A. Kuksis, N.A. Shaikh, Glucosylated glycerophosphoethanolamines
2658–2664. are the major LDL glycation products and increase LDL susceptibility to oxidation:
[166] B.H. Chung, et al., Liposome-like particles isolated from human atherosclerotic evidence of their presence in atherosclerotic lesions, Arterioscler. Thromb. Vasc.
plaques are structurally and compositionally similar to surface remnants of Biol. 20 (2) (2000) 467–477.
triglyceride-rich lipoproteins, Arterioscler. Thromb. 14 (4) (1994) 622–635. [194] E. Hurt-Camejo, et al., Cellular consequences of the association of apoB
[167] J.H. Rapp, et al., Triglyceride-rich lipoproteins isolated by selected-affinity anti- lipoproteins with proteoglycans. Potential contribution to atherogenesis,
apolipoprotein B immunosorption from human atherosclerotic plaque, Arterioscler. Thromb. Vasc. Biol. 17 (6) (1997) 1011–1017.
Arterioscler. Thromb. 14 (11) (1994) 1767–1774. [195] R.L. Silverstein, M. Febbraio, CD36, a scavenger receptor involved in immunity,
[168] S.D. Proctor, D.F. Vine, J.C. Mamo, Arterial permeability and efflux of metabolism, angiogenesis, and behavior, Sci. Signal. 2 (72) (2009) re3.
apolipoprotein B-containing lipoproteins assessed by in situ perfusion and three- [196] A. Ravandi, A. Kuksis, N.A. Shaikh, Glycated phosphatidylethanolamine promotes
dimensional quantitative confocal microscopy, Arterioscler. Thromb. Vasc. Biol. macrophage uptake of low density lipoprotein and accumulation of cholesteryl
24 (11) (2004) 2162–2167. esters and triacylglycerols, J. Biol. Chem. 274 (23) (1999) 16494–16500.
[169] C. Flood, et al., Identification of the proteoglycan binding site in apolipoprotein [197] B.E. Brown, R.T. Dean, M.J. Davies, Glycation of low-density lipoproteins by
B48, J. Biol. Chem. 277 (35) (2002) 32228–32233. methylglyoxal and glycolaldehyde gives rise to the in vitro formation of lipid-
[170] K.H. Weisgraber, et al., Human apolipoprotein E. Determination of the heparin laden cells, Diabetologia 48 (2) (2005) 361–369.
binding sites of apolipoprotein E3, J. Biol. Chem. 261 (5) (1986) 2068–2076. [198] B.E. Brown, et al., Hydrazine compounds inhibit glycation of low-density
[171] A. Varbo, M. Benn, B.G. Nordestgaard, Remnant cholesterol as a cause of ischemic lipoproteins and prevent the in vitro formation of model foam cells from
heart disease: evidence, definition, measurement, atherogenicity, high risk glycolaldehyde-modified low-density lipoproteins, Diabetologia 49 (4) (2006)
patients, and present and future treatment, Pharmacol. Ther. 141 (3) (2014) 775–783.
358–367. [199] S. Horiuchi, Y. Sakamoto, M. Sakai, Scavenger receptors for oxidized and glycated
[172] M. Umaerus, et al., HDL2 interferes with LDL association with arterial proteins, Amino Acids 25 (3–4) (2003) 283–292.
proteoglycans: a possible athero-protective effect, Atherosclerosis 225 (1) (2012) [200] Y. Jinnouchi, et al., Glycolaldehyde-modified low density lipoprotein leads
115–120. macrophages to foam cells via the macrophage scavenger receptor, J. Biochem.
[173] N. Rabbani, et al., Glycation of LDL by methylglyoxal increases arterial 123 (6) (1998) 1208–1217.
atherogenicity: a possible contributor to increased risk of cardiovascular disease [201] B.E. Brown, et al., Glycation of low-density lipoprotein results in the time-
in diabetes, Diabetes 60 (7) (2011) 1973–1980. dependent accumulation of cholesteryl esters and apolipoprotein B-100 protein in
[174] I.J. Edwards, et al., Glycation of plasma low density lipoproteins increases primary human monocyte-derived macrophages, FEBS J. 274 (6) (2007)
interaction with arterial proteoglycans, Diabetes Res. Clin. Pract. 46 (1) (1999) 1530–1541.
9–18. [202] A. Pirillo, G.D. Norata, A.L. Catapano, LOX-1, OxLDL, and atherosclerosis, Mediat.
[175] F.M. Sacks, et al., VLDL, apolipoproteins B, CIII, and E, and risk of recurrent Inflamm. 2013 (2013) 152786.
coronary events in the Cholesterol and Recurrent Events (CARE) trial, Circulation [203] M.C. Lam, K.C. Tan, K.S. Lam, Glycoxidized low-density lipoprotein regulates the
102 (16) (2000) 1886–1892. expression of scavenger receptors in THP-1 macrophages, Atherosclerosis 177 (2)
[176] K. Olin-Lewis, et al., ApoC-III content of apoB-containing lipoproteins is (2004) 313–320.
associated with binding to the vascular proteoglycan biglycan, J. Lipid Res. 43 [204] Y. Iwashima, et al., Advanced glycation end products-induced gene expression of
(11) (2002) 1969–1977. scavenger receptors in cultured human monocyte-derived macrophages, Biochem.
[177] A. Hiukka, et al., ApoCIII-enriched LDL in type 2 diabetes displays altered lipid Biophys. Res. Commun. 277 (2) (2000) 368–380.
composition, increased susceptibility for sphingomyelinase, and increased [205] S. Yui, et al., Induction of macrophage growth by advanced glycation end
binding to biglycan, Diabetes 58 (9) (2009) 2018–2026. products of the Maillard reaction, J. Immunol. 152 (4) (1994) 1943–1949.
[178] L.R. Tannock, A. Chait, Lipoprotein-matrix interactions in macrovascular disease [206] Y. Iwashima, et al., Advanced glycation end product-induced peroxisome
in diabetes, Front. Biosci. 9 (2004) 1728–1742. proliferator-activated receptor gamma gene expression in the cultured mesangial
[179] K. Skålén, et al., Subendothelial retention of atherogenic lipoproteins in early cells, Biochem. Biophys. Res. Commun. 264 (2) (1999) 441–448.
atherosclerosis, Nature 417 (6890) (2002) 750–754. [207] K. Fukuhara-Takaki, et al., Expression of class A scavenger receptor is enhanced
[180] E. Hurt-Camejo, et al., Localization of nonpancreatic secretory phospholipase A2 by high glucose in vitro and under diabetic conditions in vivo: one mechanism for
in normal and atherosclerotic arteries. Activity of the isolated enzyme on low- an increased rate of atherosclerosis in diabetes, J. Biol. Chem. 280 (5) (2005)
density lipoproteins, Arterioscler. Thromb. Vasc. Biol. 17 (2) (1997) 300–309. 3355–3364.
[181] P. Sartipy, et al., Binding of human phospholipase A2 type II to proteoglycans. [208] S.C. Whitman, et al., Uptake of type III hypertriglyceridemic VLDL by
Differential effect of glycosaminoglycans on enzyme activity, J. Biol. Chem. 271 macrophages is enhanced by oxidation, especially after remnant formation,
(42) (1996) 26307–26314. Arterioscler. Thromb. Vasc. Biol. 17 (9) (1997) 1707–1715.
[182] M. Rodriguéz-Lee, G. Bondjers, G. Camejo, Fatty acid-induced atherogenic [209] S. Tomono, et al., Uptake of remnant like particles (RLP) in diabetic patients from
changes in extracellular matrix proteoglycans, Curr. Opin. Lipidol. 18 (5) (2007) mouse peritoneal macrophages, J. Atherosclerosis Thromb. 1 (2) (1994) 98–102.
546–553.

12
L. Luciani et al. Atherosclerosis 394 (2024) 117545

[210] B.J. Van Lenten, et al., Receptor-mediated uptake of remnant lipoproteins by [239] A.P. Burke, et al., Morphologic findings of coronary atherosclerotic plaques in
cholesterol-loaded human monocyte-macrophages, J. Biol. Chem. 260 (15) diabetics: a postmortem study, Arterioscler. Thromb. Vasc. Biol. 24 (7) (2004)
(1985) 8783–8788. 1266–1271.
[211] C.H. Florén, J.J. Albers, E.L. Bierman, Uptake of chylomicron remnants causes [240] E. Fabris, et al., Thin-cap fibroatheroma rather than any lipid plaques increases
cholesterol accumulation in cultured human arterial smooth muscle cells, the risk of cardiovascular events in diabetic patients: insights from the COMBINE
Biochim. Biophys. Acta 663 (1) (1981) 336–349. OCT-FFR trial, Circ Cardiovasc Interv 15 (5) (2022) e011728.
[212] B. Bermudez, et al., Triglyceride-rich lipoprotein regulates APOB48 receptor gene [241] G.V. Sangle, et al., Involvement of RAGE, NADPH oxidase, and Ras/Raf-1
expression in human THP-1 monocytes and macrophages, J. Nutr. 142 (2) (2012) pathway in glycated LDL-induced expression of heat shock factor-1 and
227–232. plasminogen activator inhibitor-1 in vascular endothelial cells, Endocrinology
[213] K. Nakajima, T. Nakano, A. Tanaka, The oxidative modification hypothesis of 151 (9) (2010) 4455–4466.
atherosclerosis: the comparison of atherogenic effects on oxidized LDL and [242] M. Mohanan Nair, et al., Impact of glycated LDL on endothelial nitric oxide
remnant lipoproteins in plasma, Clin. Chim. Acta 367 (1–2) (2006) 36–47. synthase in vascular endothelial cells: involvement of transmembrane signaling
[214] K. Kim, et al., Transcriptome analysis reveals Nonfoamy rather than foamy plaque and endoplasmic reticulum stress, J. Diabet. Complicat. 30 (3) (2016) 391–397.
macrophages are Proinflammatory in atherosclerotic murine models, Circ. Res. [243] Y. Dong, et al., Activation of protease calpain by oxidized and glycated LDL
123 (10) (2018) 1127–1142. increases the degradation of endothelial nitric oxide synthase, J. Cell Mol. Med.
[215] J.W. Williams, et al., Limited proliferation capacity of aortic intima resident 13 (9a) (2009) 2899–2910.
macrophages requires monocyte recruitment for atherosclerotic plaque [244] S. Ren, et al., Impact of diabetes-associated lipoproteins on generation of
progression, Nat. Immunol. 21 (10) (2020) 1194–1204. fibrinolytic regulators from vascular endothelial cells, J. Clin. Endocrinol. Metab.
[216] M.R. Bennett, S. Sinha, G.K. Owens, Vascular smooth muscle cells in 87 (1) (2002) 286–291.
atherosclerosis, Circ. Res. 118 (4) (2016) 692–702. [245] J. Zhang, et al., Influence of glycation on LDL-induced generation of fibrinolytic
[217] Y. Gui, H. Zheng, R.Y. Cao, Foam cells in atherosclerosis: novel insights into its regulators in vascular endothelial cells, Arterioscler. Thromb. Vasc. Biol. 18 (7)
origins, consequences, and molecular mechanisms, Front Cardiovasc Med 9 (1998) 1140–1148.
(2022) 845942. [246] R. Zhao, G.X. Shen, Involvement of heat shock factor-1 in glycated LDL-induced
[218] P.M. Marcovecchio, et al., Scavenger receptor CD36 directs Nonclassical upregulation of plasminogen activator inhibitor-1 in vascular endothelial cells,
monocyte patrolling along the endothelium during early atherogenesis, Diabetes 56 (5) (2007) 1436–1444.
Arterioscler. Thromb. Vasc. Biol. 37 (11) (2017) 2043–2052. [247] G. Ferretti, et al., Glycated low density lipoproteins modify platelet properties: a
[219] L. Toma, et al., Caffeic acid attenuates the inflammatory stress induced by compositional and functional study, J. Clin. Endocrinol. Metab. 87 (5) (2002)
glycated LDL in human endothelial cells by mechanisms involving inhibition of 2180–2184.
AGE-receptor, oxidative, and endoplasmic reticulum stress, Biofactors 43 (5) [248] R.A. Rabini, et al., Reduced Na(+)-K(+)-ATPase activity and plasma
(2017) 685–697. lysophosphatidylcholine concentrations in diabetic patients, Diabetes 43 (7)
[220] D. Masuda, S. Yamashita, Postprandial hyperlipidemia and remnant lipoproteins, (1994) 915–919.
J. Atherosclerosis Thromb. 24 (2) (2017) 95–109. [249] D. Varga-Szabo, A. Braun, B. Nieswandt, Calcium signaling in platelets,
[221] M. Kosmopoulos, et al., Impact of advanced glycation end products (AGEs) J. Thromb. Haemostasis 7 (7) (2009) 1057–1066.
signaling in coronary artery disease, Biochim. Biophys. Acta, Mol. Basis Dis. 1865 [250] J.H. Barach, A.D. Lowy, Lipoprotein molecules cholesterol and atherosclerosis in
(3) (2019) 611–619. diabetes mellitus, Diabetes 1 (6) (1952) 441–446.
[222] L. Toma, et al., Glycated LDL increase VCAM-1 expression and secretion in [251] S.S. Levinson, Non-high-density lipoprotein cholesterol and guidelines for
endothelial cells and promote monocyte adhesion through mechanisms involving cholesterol lowering in recent history, Lab. Med. 51 (1) (2020) 14–23.
endoplasmic reticulum stress, Mol. Cell. Biochem. 417 (1–2) (2016) 169–179. [252] D.S. Dhindsa, et al., The Evolving understanding and approach to residual
[223] K. Isoda, et al., Glycated LDL increases monocyte CC chemokine receptor 2 cardiovascular risk management, Front Cardiovasc Med 7 (2020) 88.
expression and monocyte chemoattractant protein-1-mediated chemotaxis, [253] A.D. Sniderman, et al., Discordance analysis of apolipoprotein B and non-high
Atherosclerosis 198 (2) (2008) 307–312. density lipoprotein cholesterol as markers of cardiovascular risk in the
[224] J.M. Cook-Mills, M.E. Marchese, H. Abdala-Valencia, Vascular cell adhesion INTERHEART study, Atherosclerosis 225 (2) (2012) 444–449.
molecule-1 expression and signaling during disease: regulation by reactive [254] J.T. Wilkins, et al., Discordance between apolipoprotein B and LDL-cholesterol in
oxygen species and antioxidants, Antioxidants Redox Signal. 15 (6) (2011) Young Adults Predicts coronary artery calcification: the CARDIA study, J. Am.
1607–1638. Coll. Cardiol. 67 (2) (2016) 193–201.
[225] L. Toma, et al., Irreversibly glycated LDL induce oxidative and inflammatory state [255] P.R. Lawler, et al., Discordance between circulating atherogenic cholesterol mass
in human endothelial cells; added effect of high glucose, Biochem. Biophys. Res. and lipoprotein particle concentration in relation to future coronary events in
Commun. 390 (3) (2009) 877–882. women, Clin. Chem. 63 (4) (2017) 870–879.
[226] G.V. Sangle, et al., Impairment of mitochondrial respiratory chain activity in [256] A.D. Sniderman, et al., Apolipoprotein B particles and cardiovascular disease: a
aortic endothelial cells induced by glycated low-density lipoprotein, Free Radic. Narrative review, JAMA Cardiol 4 (12) (2019) 1287–1295.
Biol. Med. 48 (6) (2010) 781–790. [257] A. Chait, et al., Lipid-lowering in diabetes: an update, Atherosclerosis (2023)
[227] L. Wang, et al., Triglyceride-rich lipoprotein lipolysis releases neutral and 117313.
oxidized FFAs that induce endothelial cell inflammation, J. Lipid Res. 50 (2) [258] A. Das Pradhan, et al., Triglyceride lowering with pemafibrate to reduce
(2009) 204–213. cardiovascular risk, N. Engl. J. Med. 387 (21) (2022) 1923–1934.
[228] Y. Maeno, et al., IDL can stimulate atherogenic gene expression in cultured [259] D.L. Bhatt, et al., Cardiovascular risk reduction with icosapent ethyl for
human vascular endothelial cells, Diabetes Res. Clin. Pract. 48 (2) (2000) hypertriglyceridemia, N. Engl. J. Med. 380 (1) (2019) 11–22.
127–138. [260] J.C. Tardif, et al., Apolipoprotein C-III reduction in subjects with moderate
[229] A. Kawakami, et al., Apolipoprotein CIII induces expression of vascular cell hypertriglyceridaemia and at high cardiovascular risk, Eur. Heart J. 43 (14)
adhesion molecule-1 in vascular endothelial cells and increases adhesion of (2022) 1401–1412.
monocytic cells, Circulation 114 (7) (2006) 681–687. [261] D. Gaudet, et al., RNA interference therapy targeting apolipoprotein C-III in
[230] L. Xu, et al., Foamy monocytes form early and contribute to nascent hypertriglyceridemia, NEJM Evid 2 (12) (2023). EVIDoa2200325.
atherosclerosis in mice with hypercholesterolemia, Arterioscler. Thromb. Vasc. [262] Z. Ahmad, et al., Inhibition of angiopoietin-like protein 3 with a monoclonal
Biol. 35 (8) (2015) 1787–1797. antibody reduces triglycerides in hypertriglyceridemia, Circulation 140 (6)
[231] J. Cervantes, J.E. Kanter, Monocyte and macrophage foam cells in diabetes- (2019) 470–486.
accelerated atherosclerosis, Front Cardiovasc Med 10 (2023) 1213177. [263] G.F. Watts, et al., RNA interference targeting ANGPTL3 for triglyceride and
[232] M.F. Saja, et al., Triglyceride-rich lipoproteins modulate the distribution and cholesterol lowering: phase 1 basket trial cohorts, Nat. Med. 29 (9) (2023)
Extravasation of Ly6C/Gr1(low) monocytes, Cell Rep. 12 (11) (2015) 1802–1815. 2216–2223.
[233] C. Morgantini, et al., Anti-inflammatory and antioxidant properties of HDLs are [264] R.H. Jani, et al., A multicenter, prospective, randomized, double-blind study to
impaired in type 2 diabetes, Diabetes 60 (10) (2011) 2617–2623. evaluate the safety and efficacy of Saroglitazar 2 and 4 mg compared with
[234] R.A.K. Srivastava, Dysfunctional HDL in diabetes mellitus and its role in the placebo in type 2 diabetes mellitus patients having hypertriglyceridemia not
pathogenesis of cardiovascular disease, Mol. Cell. Biochem. 440 (1–2) (2018) controlled with atorvastatin therapy (PRESS VI), Diabetes Technol. Therapeut. 16
167–187. (2) (2014) 63–71.
[235] J. Apro, et al., Impaired cholesterol efflux capacity of high-density lipoprotein [265] M.S. Siddiqui, et al., Saroglitazar, a dual PPAR α/γ agonist, improves atherogenic
isolated from interstitial fluid in type 2 diabetes mellitus-Brief report, dyslipidemia in patients with non-Cirrhotic nonalcoholic fatty liver disease: a
Arterioscler. Thromb. Vasc. Biol. 36 (5) (2016) 787–791. Pooled analysis, Clin. Gastroenterol. Hepatol. 21 (10) (2023) 2597–2605.e2.
[236] C.C. Hedrick, et al., Glycation impairs high-density lipoprotein function, [266] V. Pai, et al., A multicenter, prospective, randomized, double-blind study to
Diabetologia 43 (3) (2000) 312–320. evaluate the safety and efficacy of saroglitazar 2 and 4 mg compared to
[237] S. Taguchi, T. Oinuma, T. Yamada, A comparative study of cultured smooth Pioglitazone 45 mg in diabetic dyslipidemia (PRESS V), J. Diabetes Sci. Technol. 8
muscle cell proliferation and injury, utilizing glycated low density lipoproteins (1) (2014) 132–141.
with slight oxidation, auto-oxidation, or extensive oxidation, J. Atherosclerosis [267] M.G. Wulffelé, et al., The effect of metformin on blood pressure, plasma
Thromb. 7 (3) (2000) 132–137. cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review,
[238] K. Yahagi, et al., Pathology of human coronary and carotid artery atherosclerosis J. Intern. Med. 256 (1) (2004) 1–14.
and vascular calcification in diabetes mellitus, Arterioscler. Thromb. Vasc. Biol.
37 (2) (2017) 191–204.

13