HDL

**Structure and apolipoproteins** - Densest lipoprotein (highest protein:lipid ratio), smallest in size. - Main apolipoprotein: ApoA-I (activates LCAT). It also carries ApoC-II and ApoE, which it donates to chylomicrons and VLDL. - Synthesized by the liver and intestine as nascent (discoidal) HDL, which is lipid-poor.

**Reverse cholesterol transport** 1. Nascent HDL (ApoA-I) picks up free cholesterol from peripheral cells and macrophages via ABCA1. Mutations cause Tangier disease. 2. LCAT (lecithin-cholesterol acyltransferase) esterifies the cholesterol, trapping it in the core and forming mature, spherical HDL. 3. Cholesterol esters are delivered to the liver by SR-B1 (direct uptake). Alternatively, CETP transfers them to VLDL/IDL/LDL in exchange for triglycerides, and those particles are then cleared by the liver.

**Other functions** - Reservoir of ApoC-II and ApoE for other lipoproteins. - Antioxidant, anti-inflammatory, and endothelial-protective effects.

**Reference ranges (fasting)** - Low HDL: <40 mg/dL in men, <50 mg/dL in women. - HDL >60 mg/dL is a "negative risk factor" in older ASCVD risk calculations.

**Factors that raise HDL** - Exercise - Moderate alcohol intake - Estrogen - Niacin (the most effective drug) - Fibrates (modest) - Statins (modest)

**Factors that lower HDL** - Smoking - Obesity and insulin resistance/metabolic syndrome (with high TG) - Sedentary lifestyle - Anabolic steroids - Beta-blockers, thiazides (minor effect) - Genetic: ApoA-I mutations, LCAT deficiency, Tangier disease (ABCA1 defect, with orange tonsils, hepatosplenomegaly, and peripheral neuropathy)

**Clinical significance** - Low HDL is part of metabolic syndrome and atherogenic dyslipidemia (high TG, small dense LDL, low HDL). - Mendelian randomization and trials show that raising HDL with niacin (AIM-HIGH, HPS2-THRIVE) or CETP inhibitors (torcetrapib, dalcetrapib, evacetrapib) did not reduce CV events. HDL is therefore a risk marker, not a treatment target. LDL-C remains the primary target. - CETP deficiency causes very high HDL, which is not clearly protective. - LCAT deficiency causes corneal opacities, anemia, and renal disease. - Familial hypoalphalipoproteinemia means low HDL due to ApoA-I problems.

**Step 1 pearls** - Think "HDL = Healthy/Happy" for the lipoprotein that removes cholesterol, versus LDL = "Lousy." - Know the chain: ApoA-I → LCAT → CETP → liver. - Niacin raises HDL the most by decreasing its catabolism. It also lowers LDL and TG, and its side effects are flushing (prostaglandin-mediated, reduced by aspirin), hyperglycemia, and hyperuricemia.