very low-density lipoprotein

**Origin and composition** - Made by hepatocytes from endogenously synthesized triglycerides (TGs), mostly from de novo lipogenesis driven by carbohydrate, alcohol, and insulin. Free fatty acids from adipose tissue also contribute. - About 50–60% TG by mass, with some cholesterol esters and phospholipids. - Apolipoproteins: - **ApoB-100**: structural, required for assembly and secretion. It is loaded with lipid by microsomal triglyceride transfer protein (MTP). - **ApoC-II**: acquired from HDL in the circulation. It activates lipoprotein lipase (LPL). - **ApoE**: acquired from HDL. It mediates hepatic uptake of remnants (IDL) via the LDL receptor and LRP.

**Metabolism (endogenous pathway)** 1. The liver secretes nascent VLDL. 2. VLDL picks up apoC-II and apoE from HDL. 3. LPL on capillary endothelium (adipose, muscle) hydrolyzes TGs, releasing fatty acids for storage or energy. 4. VLDL shrinks to IDL (VLDL remnant). About half of IDL is taken up by the liver via apoE. The rest loses more TG through hepatic lipase and becomes **LDL** (cholesterol-rich, apoB-100 only). 5. CETP exchanges TG from VLDL for cholesterol esters from HDL.

**Clinical significance** - **Familial hypertriglyceridemia (type IV)**: autosomal dominant, with overproduction of VLDL. Labs show elevated VLDL and TG, and the serum is cloudy. It is associated with pancreatitis when TG is above about 1000 mg/dL. - **Type III (dysbetalipoproteinemia)**: apoE2/E2 defect causes remnant (IDL/chylomicron remnant) accumulation. Findings are palmar/tuberoeruptive xanthomas and premature atherosclerosis. - **Type V (mixed)**: elevated VLDL and chylomicrons. - **LPL or apoC-II deficiency (type I)**: chylomicronemia. VLDL can be elevated, with eruptive xanthomas, lipemia retinalis, and pancreatitis. - **Abetalipoproteinemia**: MTP defect, so apoB-100/48 lipoproteins are not assembled. Chylomicrons, VLDL, and LDL are absent. Findings are fat malabsorption, acanthocytes, steatorrhea, vitamin E deficiency (ataxia, retinitis pigmentosa), and intestinal enterocyte lipid accumulation. - **Secondary causes of high VLDL**: diabetes mellitus and insulin resistance, obesity, alcohol, hypothyroidism, nephrotic syndrome, and drugs (estrogen, β-blockers, thiazides, corticosteroids, protease inhibitors). - **Metabolic syndrome and NAFLD**: increased hepatic VLDL output is part of atherogenic dyslipidemia (high TG, low HDL, small dense LDL). - **Estimating LDL**: Friedewald equation LDL = TC − HDL − (TG/5). VLDL ≈ TG/5, and this is invalid when TG is above 400 mg/dL.

**Treatment of high VLDL/TG** - Lifestyle: weight loss, reducing refined carbohydrates and alcohol, and exercise. - **Fibrates** (gemfibrozil, fenofibrate): PPAR-α agonists that increase LPL activity. They are the most effective for lowering TG. Adverse effects are myopathy (especially with statins) and cholesterol gallstones. - **Niacin**: decreases hepatic VLDL secretion. It causes flushing (prostaglandin-mediated, reduced by aspirin), hyperglycemia, and hyperuricemia. - **Omega-3 fatty acids** reduce hepatic TG synthesis and VLDL secretion. - Statins modestly lower TG.

**High-yield comparison** - Chylomicrons carry **dietary** TG (apoB-48), and VLDL carries **endogenous** TG (apoB-100). - Both are cleared by LPL and need apoC-II. - Lipoprotein density (lowest to highest): chylomicron < VLDL < IDL < LDL < HDL.