LDL

**Structure & metabolism** - Core: cholesteryl esters (predominant) with some triglycerides; surface: phospholipids, free cholesterol, and ApoB-100. - Formation: Liver secretes VLDL (ApoB-100, ApoE, ApoC-II) → lipoprotein lipase (activated by ApoC-II) removes TGs → IDL → hepatic lipase converts IDL to LDL. - Uptake: ApoB-100 binds LDL receptors (hepatic ~70%, and peripheral) → clathrin-mediated endocytosis → lysosomal degradation → free cholesterol released. Intracellular cholesterol: downregulates HMG-CoA reductase, downregulates LDL receptor synthesis, and activates ACAT (cholesterol esterification for storage). - PCSK9 promotes LDL receptor degradation, which raises LDL-C. - LCAT (activated by ApoA-I) esterifies cholesterol on HDL; CETP transfers cholesteryl esters from HDL to VLDL/LDL.

**Pathophysiology of atherosclerosis** - Small, dense LDL is oxidized in the intima → taken up by macrophage scavenger receptors → foam cells → fatty streak → fibrous plaque. - Oxidized LDL drives endothelial dysfunction, inflammation, and smooth muscle migration.

**Clinical associations** - Familial hypercholesterolemia (type IIa): AD, LDL receptor defect (most common), ApoB-100 defect (familial defective ApoB-100), or PCSK9 gain-of-function. Features: ↑↑ LDL, normal TG, tendon (Achilles) xanthomas, xanthelasma, corneal arcus, premature CAD. Heterozygotes: LDL ~300 mg/dL; homozygotes: >600 mg/dL with MI in childhood. - Abetalipoproteinemia: MTP deficiency → no ApoB-containing lipoproteins (no chylomicrons, VLDL, LDL) → fat malabsorption, acanthocytes, ataxia, retinitis pigmentosa, fat-soluble vitamin deficiency. - Secondary causes of ↑ LDL: hypothyroidism, nephrotic syndrome, cholestasis, diet high in saturated/trans fat, and drugs (thiazides, beta-blockers, cyclosporine, and others).

**Lab/Measurement** - Friedewald equation: LDL = TC − HDL − (TG/5) (invalid if TG >400 mg/dL). Also measured directly or by Martin-Hopkins/Sampson equations. - Non-HDL cholesterol (TC − HDL) and ApoB are useful when TG is high. - General targets (ACC/AHA): optimal <100 mg/dL; LDL ≥190 mg/dL is severe hypercholesterolemia that warrants treatment regardless of risk score. Targets are lower with established ASCVD (e.g., <70 mg/dL, or lower in very high-risk patients).

**Treatment (by effect on LDL)** - Statins (HMG-CoA reductase inhibitors; ↓LDL 20–60%): upregulate hepatic LDL receptors. Adverse effects: hepatotoxicity, myopathy/rhabdomyolysis (risk ↑ with fibrates, niacin, or CYP3A4 inhibitors). - Ezetimibe (blocks NPC1L1 cholesterol absorption): ↓LDL ~18%. - PCSK9 inhibitors (evolocumab, alirocumab): ↓LDL ~60%; used in FH or statin-intolerant/very high-risk patients. Inclisiran (siRNA against PCSK9) is dosed less frequently. - Bile acid sequestrants (cholestyramine, colestipol, colesevelam): ↓LDL but may ↑TG; cause bloating and decreased absorption of fat-soluble vitamins and other drugs. - Bempedoic acid (ATP-citrate lyase inhibitor): ↓LDL; may cause hyperuricemia/gout and tendon rupture. - Lomitapide (MTP inhibitor) and mipomersen (ApoB antisense) are used in homozygous FH; risk of hepatic steatosis. - Niacin: ↓LDL modestly, ↑HDL; flushing (prostaglandin-mediated; reduced by aspirin), hyperglycemia, hyperuricemia. - Fibrates mainly ↓TG, with minimal LDL effect.

**Board pearls** - LDL carries the most cholesterol to peripheral tissues; HDL performs reverse cholesterol transport. - ApoB-100 is the ligand for the LDL receptor; ApoE is the ligand for remnant (IDL/chylomicron remnant) uptake. - Tendon xanthomas + elevated LDL = think familial hypercholesterolemia.