Chapter 11  ·  Module 1

Lipids, Lipoproteins, and Cardiovascular Risk

Visual summary — lipoprotein classes, metabolic pathways, and drug targets

Lipoprotein Classes — Structure and Role

Dietary pathway

Chylomicrons

  • Made in intestine after fat absorption
  • Carry apolipoprotein B-48
  • Largest, least dense lipoprotein
  • Remnants are atherogenic

Endogenous pathway

Very Low-Density Lipoprotein → Low-Density Lipoprotein

  • Very low-density lipoprotein: liver exports triglycerides
  • Carries apolipoprotein B-100, apolipoprotein C-II, apolipoprotein E
  • Remodeled by lipoprotein lipase to low-density lipoprotein
  • Low-density lipoprotein: primary atherogenic particle

Reverse transport

High-Density Lipoprotein

  • Carries apolipoprotein A-I
  • Collects cholesterol from peripheral tissues
  • Returns cholesterol to liver for excretion
  • Risk marker — not a drug target

The Endogenous Pathway — From Very Low-Density Lipoprotein to Low-Density Lipoprotein

Liver

Very Low-Density Lipoprotein

Secreted with triglycerides and apolipoprotein B-100

→

Lipoprotein lipase

Triglyceride hydrolysis

Activated by apolipoprotein C-II on particle surface

→

Intermediate form

Intermediate-Density Lipoprotein

Transient; further remodeled

→

Primary target

Low-Density Lipoprotein

Cholesterol-enriched; cleared by low-density lipoprotein receptor

Low-Density Lipoprotein Receptor — Regulation and Drug Targets

Statins

Block cholesterol synthesis

  • Inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase
  • Hepatic cholesterol falls
  • Low-density lipoprotein receptor expression increases
  • More low-density lipoprotein cleared from plasma

Ezetimibe

Block intestinal absorption

  • Inhibits Niemann-Pick C1-Like 1 transporter
  • Less cholesterol delivered to liver
  • Compensatory low-density lipoprotein receptor upregulation
  • Additive to statin effect

Proprotein convertase subtilisin/kexin type 9 inhibitors

Prevent receptor degradation

  • Block proprotein convertase subtilisin/kexin type 9 from destroying receptors
  • More receptors recycle to cell surface
  • Maximum low-density lipoprotein clearance
  • Additive to statin and ezetimibe

Secondary Causes of Dyslipidemia — Screen Before Prescribing

Cause Effect on Low-Density Lipoprotein Effect on Triglycerides Effect on High-Density Lipoprotein Key Screening Test
Hypothyroidism Elevated Variable Normal or low Thyroid-stimulating hormone
Type 2 diabetes / insulin resistance Normal or mildly elevated Elevated Low Fasting glucose, hemoglobin A1c
Nephrotic syndrome Markedly elevated Elevated Low Urine protein
Thiazides / beta-blockers Variable Elevated Low Medication review
Glucocorticoids Elevated Elevated Variable Medication review

Clinical Rule

Always exclude secondary causes — particularly hypothyroidism, uncontrolled diabetes, nephrotic syndrome, and causative drugs — before initiating or escalating lipid-lowering pharmacotherapy. Treating the lipid without correcting the cause produces suboptimal results and may delay diagnosis of a treatable condition.