Lipid Transport & Dyslipidemias

Lipoprotein particles and apolipoproteins

Five particles, from fluffy to dense. In order of increasing density: chylomicron (most triglyceride, least dense), VLDL, IDL, LDL, and HDL (most dense, most protein). Chylomicrons carry dietary fat from the gut; VLDL carries fat made in the liver; LDL delivers cholesterol to tissues; HDL retrieves it.

Apolipoproteins are the address labels.

• ApoB-48 — chylomicron assembly and secretion from the gut.
• ApoB-100 — binds the LDL receptor; on VLDL, IDL, and LDL.
• ApoC-II — activates lipoprotein lipase.
• ApoE — mediates hepatic uptake of remnants (chylomicron remnants, IDL).
• ApoA-I — the main HDL protein; activates LCAT.

B-48 for Bowel; B-100 Binds the LDL receptor; C-II is the Cofactor for LPL; E for Extra (remnant) uptake.

How lipids are delivered and retrieved

Lipoprotein lipase (LPL). LPL sits on capillary endothelium (notably in adipose tissue and muscle) and hydrolyzes triglycerides in chylomicrons and VLDL, releasing free fatty acids for the tissues. It is activated by ApoC-II and released into the blood by heparin. Chylomicron remnants are then cleared by the liver via ApoE. Hepatic lipase converts IDL to LDL.

LDL receptor. Hepatic and peripheral LDL receptors bind ApoB-100 (and ApoE) and internalize LDL and remnants by receptor-mediated endocytosis. Defective receptors cause familial hypercholesterolemia.

PCSK9. PCSK9 binds the LDL receptor and targets it for lysosomal degradation, so it RAISES serum LDL. PCSK9 inhibitors (evolocumab, alirocumab) spare the receptor for recycling and drop LDL sharply. Loss-of-function PCSK9 mutations cause naturally low LDL and cardioprotection, which inspired the drug class; gain-of-function mutations cause an FH phenotype.

HDL, the cholesterol vacuum. HDL (ApoA-I) mediates reverse cholesterol transport, carrying cholesterol from the periphery back to the liver, and serves as a reservoir of ApoC-II and ApoE for other particles. Nascent HDL is loaded with cholesterol through the ABCA1 transporter (defective in Tangier disease, with very low HDL). LCAT esterifies cholesterol inside HDL so it can be carried in the core; CETP swaps cholesteryl esters from HDL to VLDL/LDL in exchange for triglyceride.

Familial dyslipidemias

First triage. Is the problem triglyceride-driven (types I and IV, with pancreatitis risk) or cholesterol/LDL-driven (type IIa, with atherosclerosis risk)? Then name the molecule. Type III sits between, with remnant particles and premature atherosclerosis.

Type I — hyperchylomicronemia. LPL or ApoC-II deficiency (autosomal recessive) massively elevates chylomicrons and triglycerides, often above 1,000 mg/dL. Plasma forms a creamy supernatant; patients have eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, and recurrent acute pancreatitis — notably with NO increased atherosclerosis risk.

Type IIa — familial hypercholesterolemia (FH). A defective LDL receptor (or ApoB-100), autosomal dominant, raises LDL and total cholesterol. Findings: tendon (Achilles) xanthomas, xanthelasma, corneal arcus at a young age, and premature atherosclerosis. Homozygotes have MI in childhood. Drugs that act by upregulating LDL receptors (statins, PCSK9 inhibitors) work well in heterozygotes; receptor-negative homozygotes may need LDL apheresis.

Type III — familial dysbetalipoproteinemia. Defective ApoE (E2/E2) impairs remnant clearance, raising chylomicron remnants and VLDL remnants (a "broad beta" band on electrophoresis). It causes premature atherosclerosis and palmar crease and tuberoeruptive xanthomas; expression usually needs a second hit such as obesity, diabetes, or hypothyroidism.

Type IV — hypertriglyceridemia. Hepatic overproduction of VLDL (autosomal dominant) elevates VLDL and triglycerides, often with insulin resistance. Very high triglycerides risk acute pancreatitis.

Abetalipoproteinemia

No MTP, no ApoB particles. Loss of microsomal triglyceride transfer protein (MTP), autosomal recessive, prevents enterocytes and liver from assembling ApoB-containing particles, so there are no chylomicrons, VLDL, or LDL; plasma ApoB and cholesterol are nearly undetectable. It is the opposite of the other disorders here — near-absent lipoproteins rather than excess.

Presentation. In infancy: failure to thrive, steatorrhea and fat malabsorption, acanthocytes (spiculated red cells), and fat-soluble vitamin deficiency. Intestinal biopsy shows enterocytes stuffed with trapped lipid. Vitamin E deficiency drives the progressive ataxia (spinocerebellar degeneration) and retinitis pigmentosa.

Treat with high-dose vitamin E (plus other fat-soluble vitamins) and restriction of long-chain fats.