LDL cholesterol

**Formation/metabolism:** Hepatic VLDL (apoB-100, apoC-II, apoE) is secreted into blood -> lipoprotein lipase (LPL, activated by apoC-II) removes triglycerides -> IDL -> hepatic lipase converts IDL to LDL (apoB-100 only; ~cholesteryl-ester-rich core). LDL delivers cholesterol to liver and peripheral tissues via LDL receptor (LDLR)-mediated endocytosis, recognizing apoB-100 (and apoE on remnants). Intracellular cholesterol suppresses HMG-CoA reductase and LDLR synthesis (SREBP-2 regulated) and activates ACAT (esterification).

**PCSK9:** Promotes lysosomal degradation of LDLR. Gain-of-function mutations -> high LDL; loss-of-function -> low LDL and protection from CAD. PCSK9 inhibitors (evolocumab, alirocumab; inclisiran = siRNA) lower LDL substantially.

**Pathophysiology of atherosclerosis:** LDL enters the subendothelium, is oxidized (oxLDL), taken up by macrophages via scavenger receptors -> foam cells -> fatty streak -> fibrous plaque -> complicated plaque (rupture, thrombosis -> MI, stroke).

**Clinical significance/associations:** - **Familial hypercholesterolemia (type IIa):** AD; LDLR defect (most common), also ApoB-100 or PCSK9 gain-of-function mutations. Heterozygotes: LDL ~300 mg/dL, tendon (Achilles) xanthomas, corneal arcus, premature CAD (~30s-40s). Homozygotes: LDL >700 mg/dL, MI in childhood/teens. - **Abetalipoproteinemia:** absent apoB-48/100 -> very low LDL, fat malabsorption, acanthocytes, ataxia, retinitis pigmentosa (vit E/A deficiency). - **Secondary causes of high LDL:** hypothyroidism, nephrotic syndrome, cholestasis, Cushing, high saturated/trans-fat diet, medications (thiazides, some antiretrovirals, cyclosporine). - **Friedewald equation:** LDL = TC − HDL − (TG/5) (invalid if TG >400 mg/dL; use direct measurement or Martin-Hopkins/Sampson).

**Targets/treatment (ACC/AHA approach):** - Statin (HMG-CoA reductase inhibitors): first-line; ↓LDL most (also ↑LDLR expression); side effects: myopathy/rhabdo, hepatotoxicity. Indications: clinical ASCVD, LDL ≥190 mg/dL, diabetes age 40-75, or elevated 10-year risk. - Ezetimibe: ↓ intestinal cholesterol absorption (NPC1L1); add-on. - Bile acid resins (cholestyramine, colestipol, colesevelam): ↓LDL, but may ↑TG; bind other drugs; GI side effects. - PCSK9 inhibitors; bempedoic acid (ATP-citrate lyase inhibitor); lomitapide (MTP inhibitor, for HoFH); niacin (modest ↓LDL, mainly ↑HDL). - Very high-risk ASCVD often aims for LDL <55-70 mg/dL.

**Classification (adult, mg/dL):** optimal <100; near-optimal 100-129; borderline high 130-159; high 160-189; very high ≥190.

**High-yield pearls:** LDL is "bad cholesterol"; apoB-100 is the ligand for LDLR; small dense LDL is more atherogenic; Lp(a) is an LDL-like particle with apo(a) (plasminogen homolog) that is an independent CAD risk factor.