Lipid Transport — Lipoproteins, Apolipoproteins & Dyslipidaemias — USMLE Step 1 Notes

The lipoproteins (biggest/least dense → smallest/most dense)

• Chylomicrons: carry dietary triglyceride from the gut via lymph; the most triglyceride-rich and least dense. Chylomicron remnants are cleared by the liver.
• VLDL: carries liver-made (endogenous) triglyceride to tissues.
• IDL: a VLDL remnant, taken up by the liver or converted to LDL.
• LDL: the main cholesterol carrier delivered to peripheral tissues; taken up via the LDL receptor. The most atherogenic ("bad").
• HDL: performs reverse cholesterol transport, carrying cholesterol from tissues back to the liver; the most dense and protective ("good"). It is also a reservoir of apoC-II and apoE.

Major apolipoproteins & their roles

• ApoA-I: activates LCAT and is the main structural protein of HDL (drives reverse cholesterol transport).
• ApoB-48: the structural backbone of chylomicrons (made in the intestine); mediates secretion into lymph.
• ApoB-100: the structural protein of VLDL, IDL and LDL (made in the liver); the ligand recognised by the LDL receptor.
• ApoC-II: activates lipoprotein lipase so triglyceride can be unloaded from chylomicrons and VLDL.
• ApoE: mediates hepatic uptake of chylomicron remnants and IDL; the E2/E2 genotype causes type III dyslipidaemia and apoE4 raises Alzheimer risk.

Key enzymes & transfer proteins

• Lipoprotein lipase (LPL): on capillary endothelium (activated by apoC-II) — hydrolyses triglyceride in chylomicrons and VLDL, releasing free fatty acids to tissues.
• Hepatic lipase: on liver endothelium — hydrolyses triglyceride in remnants and HDL, helping convert IDL to LDL.
• LCAT (lecithin-cholesterol acyltransferase): activated by apoA-I — esterifies cholesterol on HDL so it can be carried in the core (matures HDL).
• CETP (cholesteryl ester transfer protein): transfers cholesteryl esters from HDL to VLDL/LDL in exchange for triglyceride.
• PCSK9: binds the LDL receptor and marks it for degradation; blocking PCSK9 recycles more receptors and lowers LDL.
• HMG-CoA reductase: the rate-limiting enzyme of cholesterol synthesis (the statin target).

Abetalipoproteinaemia

• Autosomal recessive defect of microsomal triglyceride transfer protein (MTP) — the enterocyte and hepatocyte cannot assemble apoB-containing lipoproteins, so no chylomicrons, VLDL or LDL form.
• Presents in infancy with fat malabsorption and steatorrhoea, failure to thrive, fat-soluble vitamin (A, D, E, K) deficiency, acanthocytes on the film, and later ataxia and retinitis pigmentosa (from vitamin E deficiency).
• Biopsy shows lipid-laden enterocytes; treat with a low-long-chain-fat diet and high-dose fat-soluble vitamins (especially vitamin E).

Familial dyslipidaemias (Fredrickson types I–IV)

• Type I — familial chylomicronaemia: LPL or apoC-II deficiency (autosomal recessive). Blood shows very high chylomicrons and triglycerides; presents with eruptive xanthomas, lipaemia retinalis, hepatosplenomegaly and acute pancreatitis. No increased atherosclerosis.
• Type IIa — familial hypercholesterolaemia: absent/defective LDL receptor (or apoB-100), autosomal dominant. High LDL and cholesterol; tendon xanthomas, xanthelasma, corneal arcus and premature coronary disease. Homozygotes present in childhood.
• Type IIb — familial combined hyperlipidaemia: hepatic overproduction of apoB/VLDL. Raised LDL and VLDL (high cholesterol and triglyceride); premature atherosclerosis.
• Type III — dysbetalipoproteinaemia: defective apoE (E2/E2), impairing remnant clearance. Raised IDL and chylomicron remnants; palmar (tuberoeruptive) xanthomas and premature atherosclerosis.
• Type IV — familial hypertriglyceridaemia: hepatic overproduction of VLDL, autosomal dominant. Raised VLDL and triglycerides; pancreatitis risk when triglycerides are very high.

Lipid-lowering pharmacology (mechanisms)

• Statins (e.g. atorvastatin): inhibit HMG-CoA reductase → less cholesterol synthesis → upregulated LDL receptors; the biggest LDL reduction and mortality benefit (watch myopathy and transaminases).
• Ezetimibe: blocks intestinal cholesterol absorption (NPC1L1); lowers LDL, additive to statins.
• PCSK9 inhibitors (e.g. alirocumab): monoclonal antibodies that prevent LDL-receptor degradation → strong LDL lowering.
• Bile-acid resins (cholestyramine): bind bile acids so the liver uses cholesterol to make more; lower LDL but can raise triglycerides and cause GI upset/malabsorption.
• Fibrates (e.g. fenofibrate): PPAR-alpha agonists that upregulate LPL → the best triglyceride lowering; used for high triglycerides (myopathy risk with statins).
• Niacin: inhibits hepatic VLDL synthesis; raises HDL and lowers LDL/triglyceride (flushing, hyperglycaemia, hyperuricaemia).
• Omega-3 fatty acids: lower triglycerides.

High-yield revision notes; verify against a primary source before clinical use.