HDL cholesterol

**Structure and apolipoproteins** - HDL is the smallest and densest lipoprotein, with the highest protein-to-lipid ratio. - Main apolipoprotein: ApoA-I, made by the liver and intestine. ApoA-I activates LCAT. - HDL also carries ApoC-II and ApoE and donates them to chylomicrons and VLDL. ApoC-II activates lipoprotein lipase.

**Metabolism and reverse cholesterol transport** 1. The liver and intestine secrete nascent (discoid) HDL, which is lipid-poor ApoA-I. 2. ABCA1 on peripheral cells (including macrophages) effluxes free cholesterol to nascent HDL. Mutations cause **Tangier disease**. 3. LCAT (lecithin-cholesterol acyltransferase) esterifies the free cholesterol. This traps it in the HDL core and produces mature, spherical HDL. 4. Mature HDL delivers cholesterol to the liver in two ways: - Directly, through SR-B1 (scavenger receptor B1) on hepatocytes. Steroidogenic tissues also take up cholesterol this way. - Indirectly, through **CETP** (cholesteryl ester transfer protein). CETP moves cholesteryl esters from HDL to VLDL/IDL/LDL in exchange for triglycerides. The liver then takes up these particles through the LDL receptor. 5. Hepatic lipase and endothelial lipase remodel HDL.

**Clinical significance** - *Reference values:* Low HDL is <40 mg/dL in men and <50 mg/dL in women. HDL ≥60 mg/dL is the traditional "negative risk factor" in the Framingham/ATP III framework. - *Epidemiology vs. causation:* HDL level is inversely associated with CAD risk. However, Mendelian randomization studies and trials of niacin (AIM-HIGH, HPS2-THRIVE) and CETP inhibitors (torcetrapib, dalcetrapib, evacetrapib) showed no CV benefit from raising HDL. HDL function (efflux capacity) may matter more than HDL-C concentration. LDL lowering remains the primary treatment target. - *Causes of low HDL:* - Lifestyle: smoking, obesity, physical inactivity, high-carbohydrate diet. - Metabolic: type 2 diabetes, insulin resistance, hypertriglyceridemia (metabolic syndrome). - Drugs: anabolic steroids, β-blockers, thiazides (variable). - Genetic: ApoA-I deficiency/mutations, **LCAT deficiency**, **Tangier disease**. Tangier disease features orange tonsils, hepatosplenomegaly, and peripheral neuropathy. LCAT deficiency features corneal opacities, hemolytic anemia, and renal failure. - *Causes of high HDL:* - Exercise. - Moderate alcohol intake. - Estrogen. - Drugs: niacin (the most effective), fibrates (modest), statins (modest). - Genetic: **CETP deficiency**, which gives very high HDL. - *Pharmacology:* Niacin (vitamin B3) raises HDL the most. It inhibits hormone-sensitive lipase in adipose tissue, which reduces hepatic VLDL synthesis. Adverse effects: flushing (prostaglandin-mediated; reduced by aspirin pretreatment), hyperglycemia, hyperuricemia (gout), and hepatotoxicity. - *Other points:* HDL is a negative acute-phase reactant. It drops during inflammation and sepsis. Estrogen raises HDL, which contributes to the lower premenopausal CAD risk in women.

**High-yield pearls** - HDL = "Happy/Healthy" cholesterol, because it removes cholesterol from tissues. - ApoA-I → LCAT activation. ApoB-100 is on LDL/VLDL/IDL. ApoB-48 is on chylomicrons. - Lipid panel: LDL is usually calculated as Friedewald LDL = TC − HDL − (TG/5). This is invalid when TG >400 mg/dL.