high-density lipoprotein

**Structure and composition:** HDL is the smallest and densest lipoprotein, with the highest protein-to-lipid ratio. Its main apolipoproteins are ApoA-I (the major structural protein and LCAT activator), ApoC-II, and ApoE. ApoC-II and ApoE are acquired from chylomicrons and VLDL, and HDL donates them back.

**Synthesis and metabolism (reverse cholesterol transport):** 1. The liver and intestine secrete nascent (discoid) HDL, which is lipid-poor and contains ApoA-I. 2. ABCA1 on peripheral cells (e.g., macrophages) transfers cholesterol and phospholipids to nascent HDL. Tangier disease results from ABCA1 mutations. 3. LCAT (lecithin-cholesterol acyltransferase), activated by ApoA-I, esterifies free cholesterol. The cholesteryl esters move into the core, which converts discoid HDL to mature spherical HDL. 4. HDL delivers cholesterol to the liver by two routes. In the direct route, HDL binds the hepatic scavenger receptor SR-B1, which takes up cholesteryl esters selectively. In the indirect route, CETP (cholesteryl ester transfer protein) swaps cholesteryl esters from HDL for triglycerides from VLDL/IDL. The cholesterol then returns to the liver in LDL and remnants.

**Other functions:** HDL acts as a reservoir for ApoC-II and ApoE. It also has antioxidant, anti-inflammatory, and endothelial-protective effects, including paraoxonase activity that limits LDL oxidation.

**Clinical significance:** - **Low HDL (<40 mg/dL) is a risk factor for ASCVD.** Causes include smoking, obesity, physical inactivity, insulin resistance/metabolic syndrome, hypertriglyceridemia, type 2 diabetes, anabolic steroids, and beta-blockers and thiazides (modest effect). Low HDL is a component of metabolic syndrome. - **High HDL (>60 mg/dL)** was historically called a "negative risk factor." Causes include exercise, moderate alcohol intake, estrogen, and CETP deficiency. Mendelian randomization studies and trials of niacin, CETP inhibitors (torcetrapib, dalcetrapib, evacetrapib), and others showed that raising HDL did not reduce cardiovascular events. Very high HDL may even be associated with higher risk. HDL function (cholesterol efflux capacity) may matter more than HDL level. - **Genetic disorders:** - **Tangier disease** (ABCA1 mutation) causes very low HDL, orange tonsils, hepatosplenomegaly, and peripheral neuropathy. - **Familial LCAT deficiency** causes corneal opacities, hemolytic anemia, and renal failure. - **ApoA-I deficiency** causes premature CAD and xanthomas. - **CETP deficiency** causes high HDL. - **Drugs affecting HDL:** Niacin raises HDL most (by decreasing hepatic catabolism of ApoA-I), but it has no proven outcome benefit. Fibrates (PPAR-α agonists that increase ApoA-I and lipoprotein lipase) raise HDL modestly. Statins raise it slightly. Lifestyle changes (exercise, smoking cessation, weight loss) are the first-line way to improve HDL.

**Board pearls:** HDL is the "good cholesterol" and the lipoprotein with the highest protein content. ApoA-I activates LCAT. Treatment goals focus on lowering LDL (and non-HDL cholesterol), not raising HDL. Estimate LDL by the Friedewald equation: LDL = TC − HDL − TG/5 (invalid when TG >400 mg/dL).