Lipoprotein

Metabolism

Department of Medicine
Malabar Medical College
 Absorption: Dietary cholesterol,
Functions fatty acids, vitamins.
of
Lipoprotein
s Transport: Liver to peripheral
tissues (TGs, cholesterol).

Reverse Transport: Cholesterol

from tissues to liver/intestine
for excretion.
 Types: Primary (genetic) or
secondary
(environmental/medical).
Disorders
of Consequences: Premature
Lipoprotein atherosclerotic
Metabolism cardiovascular disease
(ASCVD), pancreatitis.
Goal: Diagnose and
manage effectively.
 Core: Hydrophobic lipids
(TGs, cholesteryl esters).

Lipoprotei
Shell: Hydrophilic lipids
n (phospholipids, unesterified
Structure cholesterol),
apolipoproteins.
Interaction: Apolipoproteins
interface with body fluids.
 Classified by Density:
Chylomicrons, VLDL, IDL,
LDL, HDL.
Variation: Differ in size,
Lipoprotei density, and protein
n Classes content.
Lipid Content: Determines
density (lipid-rich = less
dense).
Lipoprotein
Classificatio
n

 Chylomicrons: Largest, least dense.

 HDL: Smallest, most dense.
Apolipoprote
ins Overview
 Definition: Proteins critical for
lipoprotein assembly,
function, metabolism.
 Roles: Structural support,
enzyme activation, receptor
ligands
 ApoA-I: HDL, synthesized in
liver/intestine.

ApoB-48: Chylomicrons
Major (intestine).
Apolipoprote
ins ApoB-100: VLDL/IDL/LDL
(liver).

ApoE: TG-rich particle

clearance.
 ApoB-48: Intestine, shorter
form from $APOB$ gene
(mRNA editing).
ApoB-100: Liver, full-length
ApoB protein, largest human
Variants protein.
One ApoB per particle in
apoB-containing lipoproteins.
 ApoA-I: Found on all HDL
particles.

HDL ApoA-II: Second most

Apolipoprote abundant, on ~2/3 of HDL
ins particles.

Exchange: Most
apolipoproteins (except ApoB)
swap between particles.
 Role: Transport dietary lipids from intestine.

Process: Dietary lipids hydrolyzed, absorbed

Chylomicr in small intestine, packaged into chylomicrons
with apoB-48.
on Requires: Microsomal TG transfer protein
(MTP).
Metabolis
m Delivery: Via thoracic duct to systemic
circulation.

Lipolysis: Lipoprotein lipase (LPL) on

endothelial surfaces (adipose, muscle).

Cofactors: ApoC-II (required), ApoA-V

(facilitator).
Chylomicro
n
Remnants
 Formation: TG
hydrolysis shrinks
chylomicrons,
excess lipids/apos
transfer to HDL.
 Clearance: Liver
removes
remnants via apoE
receptors.
 Role: Transport hepatic
lipids during fasting.

VLDL
Synthesis: Liver packages
Metabolis TGs with apoB-100,
m requires MTP.
Composition: TG-rich,
higher cholesterol : TG
ratio than chylomicrons.
VLDL to
LDL
Pathway
 Lipolysis: LPL
hydrolyzes VLDL
TGs, forms IDL.
 IDL Fate: 40-60%
cleared by liver
(apoE), rest
becomes LDL via
hepatic lipase
(HL).
 LDL: Primarily a
byproduct of VLDL
metabolism, minimal
LDL Role physiologic role (e.g.,
and vitamin E delivery to
Clearance Clearance: LDL receptor
retina/brain).
(apoB-100 ligand) in
liver.
 Structure: LDL-like with
apo(a) attached to apoB-
100 via disulfide bond.
Clearance: Liver, pathway
Lipoprotein unknown.
(a) [Lp(a)]

Risk: Causal factor for

ASCVD, independent risk
marker.
 Synthesis: Nascent HDL (apoA-I)
from liver/intestine.
Cholesterol Acquisition: Via
HDL ABCA1, forms discoidal HDL.
Metabolis Esterification: LCAT converts
m cholesterol to cholesteryl esters
(CE).
Maturation: CE forms HDL core,
becomes spherical.
Lipid Transfer: Gains lipids from
chylomicrons/VLDL during
lipolysis.
HDL
Metaboli
sm
 Reverse  Pathways:
Cholester o Selective uptake by liver via SR-BI.

ol o CE transfer to apoB-lipoproteins via CETP,

cleared by LDL receptor.
Transport  Excretion: Cholesterol to bile or intestine
(transintestinal).
 Proteins: PLTP
(phospholipid transfer),
CETP (TG exchange).
HDL
Enzymes: HL, endothelial
Remodeli
lipase (EL) shrink HDL.
ng

Impact: Affects HDL

metabolism and levels.
 Purpose: Identify
dyslipidemia to reduce
ASCVD risk.
Method: Fasting lipid panel
Lipid (total cholesterol, TGs,
Screening HDL-C).
LDL-C: Estimated via
Friedewald formula (if TG
<400 mg/dL).
 Non-HDL-C: Total
cholesterol - HDL-C,
includes atherogenic
Advanced lipoproteins.
ApoB: Superior to LDL-C for
Lipid risk assessment.
Markers
Lp(a): Heritable, merits
aggressive LDL-C lowering.
 Features: High total
cholesterol, TGs, and/or
Disorders LDL-C.
of Elevated
ApoB Causes: Genetic (polygenic
Lipoprotein or monogenic) + secondary
s factors.
Risk: ASCVD primary
concern.
 Definition: TG >500
mg/dL, often >1000
mg/dL.
Severe
Cause: Impaired LPL
Hypertriglyceride
mia (HTG)
activity.

Risks: Pancreatitis,
variable ASCVD risk.
 Prevalence: ~1 in 200,000-300,000.

Inheritance: Autosomal recessive.

Familial (Genes: LPL, APOC2, APOA5, GPIHBP1,

Chylomicrone LMF1).
mia Syndrome
(FCS) Features: Severe HTG, pancreatitis,
eruptive xanthomas, lipemia retinalis.
Diagnosis: Clinical (TG >500 mg/dL),
genetic testing optional.
Treatment: Fat restriction (<15 g/d),
APOC3 silencing.
Gene
defects
 Inheritance: Autosomal dominant.

Features: Abnormal fat distribution,

severe HTG.
Familial
Partial (Genes: LMNA, PPARG, PLIN1, AKT2,
ADRA2A).
Lipodystrop
hy Complications: Insulin resistance,
diabetes, ASCVD risk.
Diagnosis: Clinical + genetic testing
(optional).
Treatment: Statins, TG-lowering drugs.
 Prevalence: ~1 in 1000.

Multifactor Cause: Polygenic +

ial Severe secondary factors (obesity,
HTG diabetes, alcohol).
Management: Lifestyle,
fibrates/fish oils if TG >500
mg/dL.
 Definition: Elevated
LDL-C (>190
mg/dL).
Cause: Reduced
LDL receptor
Hypercholesterole
mia Overview

activity.
Risk: Premature
ASCVD.
 Inheritance: Autosomal dominant.

Features: High LDL-C, normal TGs.

(Genes: LDLR, APOB, PCSK9).

Familial
Hypercholesterole
mia (FH) Homozygous FH: Rare, severe LDL-C
elevation.
Diagnosis: Clinical + family history,
genetic testing.
Treatment: Early statins, PCSK9
inhibitors.
 Features: No apoB
lipoproteins, low
cholesterol/TG, vitamin E
deficiency.
Symptoms: Neurologic
Abetalipoproteine issues, retinopathy.
mia

MTTP mutations
 Features: Low LDL-C,
hepatic fat.

Homozygous: Rare,
Familial
Hypobetalipoprotein
emia (FHBL)
mimics
abetalipoproteinemia.
APOB mutations
 Features: Low LDL-
C, CHD protection.
PCSK9
Deficienc Impact: Led to
y PCSK9 inhibitor
therapies.
PCSK9 mutations
 Features: Low TG,
LDL-C, HDL-C;
Familial reduced CHD risk.
Combined Therapy: ANGPTL3
Hypolipide
mia silencing in
development.
ANGPTL3 mutations
 Definition: <40 mg/dL
(men), <50 mg/dL
(women).
Low HDL-
C Risk: Predicts ASCVD,
Overview not directly causal.

Causes: Genetic +
secondary factors.
 Features: No HDL, rare
CHD, corneal/skin
deposits.
APOA1
Deficienc Heterozygotes:
y Reduced HDL-C, no
major issues.
APOA1 mutations
 Features: Very low HDL-C
(<5 mg/dL), cholesterol
accumulation.
Symptoms: Orange tonsils,
Tangier neuropathy.
Disease
ABCA1 mutations
 Features: Low HDL-C (<10
mg/dL), high free
cholesterol.
LCAT
Types: Complete (anemia,
Deficienc renal issues) vs. partial
y (fish eye disease).
LCAT mutations
 Definition: HDL-C <10th
percentile, normal
TG/cholesterol.
Cause: Likely polygenic +
Primary
Hypoalphalipoproteinemi
secondary factors.
a

Risk: Variable ASCVD

association.
Secondary
Low HDL-C
 HTG: Impaired lipolysis
reduces HDL.
 Low-Fat Diet: Reduces
HDL-C and LDL-C.
 Sedentary
Lifestyle/Obesity: Lowers
HDL-C.
 Anabolic
Steroids/Testosterone:
Dramatic HDL-C reduction.
 Goals: Prevent pancreatitis (HTG),
ASCVD (hypercholesterolemia).
Step 1: Classify dyslipidemia (lipid
panel).
Diagnosti Step 2: Rule out secondary causes
c
Approach Severe HTG (>500 mg/dL): Consider
FCS or FPLD.
Hypercholesterolemia (>190 mg/dL):
Consider FH.
Genetic Testing: Enhances diagnosis,
family screening.
Treatment
: Severe  Reduce: Alcohol, dietary fat, simple carbs.

HTG -  Increase: Physical activity, weight loss (if

obese).
Lifestyle  Goal: TG <500 mg/dL to prevent pancreatitis.
Treatment:
Severe HTG
- Drugs

 Fibrates: ~30% TG
reduction, PPARα
agonists.
 Fish Oils: 3-4 g/d,
~30% TG
reduction.
 Reduce: Saturated/trans
fats in diet.

Treatment:
Manage: Weight,
Hypercholesterole
hypothyroidism.
mia - Lifestyle

Exercise: Limited LDL-C

impact.
Treatment:
Hypercholesterolemia -
Statins

 Mechanism: Inhibit HMG-CoA

reductase, upregulate LDL
receptors.
 Effect: 30-55% LDL-C reduction,
reduces ASCVD risk.
Treatment: Ezetimibe

Mechanism:
Effect: ~18%
Inhibits NPC1L1,
LDL-C reduction,
reduces
additive with
cholesterol
statins.
absorption.
 Mechanism: Block
PCSK9, increase
Treatmen LDL receptors.
t: PCSK9
Inhibitors
Effect: ~60% LDL-
C reduction,
subcutaneous
dosing.
 Mechanism: Inhibits
Treatmen ATP citrate lyase,
t: reduces cholesterol
Bempedoi synthesis.
c Acid
Effect: ~18-23%
LDL-C reduction,
fewer myalgias.
 Mechanism: Bind
Treatment: bile acids,
Bile Acid upregulate LDL
Sequestra
nts receptors.
Effect: LDL-C
reduction, may
increase TGs.
 Lomitapide,
mipomersen,
evinacumab
Treatmen
Lomitapide/Mipomersen:
t: HoFH Reduce VLDL, ~25-50%
Therapies LDL-C drop.
Evinacumab: ANGPTL3
inhibitor, ~50% LDL-C
reduction.
 Process: Removes LDL from
plasma extracorporeally.

Indications: LDL-C >200

LDL mg/dL (CHD) or >300
Apheresis mg/dL (no CHD) on max
therapy.
Use: Severe, unresponsive
cases.
 Tools: AHA/ACC risk
calculator, apoB, Lp(a), hs-
CRP, CAC score.
Risk Purpose: Guide statin
Stratificati initiation in primary
on prevention.
Future: Polygenic risk
scores for CAD.
 Summary: Lipoprotein disorders
are diverse, linked to
ASCVD/pancreatitis, treatable
with lifestyle/drugs.
Importance: Early screening,
Conclusio genetic insights improve
n outcomes.

Call to Action: Promote

systematic lipid management.