endocrine and metabolic disorders
Overview of Lipid Metabolism
Physiology of Lipid Metabolism
Pathway defects in lipoprotein synthesis, processing, and clearance can lead to accumulation of atherogenic lipids in plasma and endothelium. Over 95% of dietary lipids are Triglycerides (TGs) The remaining about 5% of dietary lipids are Cholesterol (present in foods as esterified cholesterol) Fat-soluble vitamins Free fatty acids (FFAs) Phospholipids Dietary TG metabolism begins in the stomach and duodenum, where TGs are broken into monoglycerides (MGs) and FFAs by gastric lipase, emulsification due to vigorous stomach peristalsis, and pancreatic lipase. Dietary cholesterol esters are de-esterified into free cholesterol by these same mechanisms. Monoglycerides, FFAs, and free cholesterol are then solubilized in the intestine by bile acid micelles, which shuttle them to intestinal villi for absorption. Once absorbed into enterocytes, they are reassembled into TGs and packaged with cholesterol into chylomicrons, the largest lipoproteins. Chylomicrons transport dietary TGs and cholesterol from within enterocytes through lymphatics into the circulation. In the capillaries of adipose and muscle tissue, apoprotein C-II (apo C-II) on the chylomicron activates endothelial lipoprotein lipase (LPL) to convert 90% of chylomicron triglyceride to fatty acids and glycerol, which are taken up by adipocytes and muscle cells for energy use or storage. Cholesterol-rich chylomicron remnants then circulate back to the liver, where they are cleared in a process mediated by apoprotein E (apo E). Lipoproteins synthesized by the liver transport endogenous triglycerides and cholesterol. Lipoproteins circulate through the blood continuously until the TGs they contain are taken up by peripheral tissues or the lipoproteins themselves are cleared by the liver. Factors that stimulate hepatic lipoprotein synthesis generally lead to elevated plasma cholesterol and TG levels. contain apoprotein B-100 (apo B), are synthesized in the liver, and transport TGs and cholesterol to peripheral tissues. VLDL is the way the liver exports excess TGs derived from plasma free fatty acids and chylomicron remnants. VLDL synthesis increases when intrahepatic FFAs increase, such as occur with high-fat diets and when excess adipose tissue releases FFAs directly into the circulation (eg, in Obesity , uncontrolled Intermediate-density lipoproteins (IDL)are the product of LPL processing of VLDL. IDL are cholesterol-rich VLDL remnants that are either cleared by the liver or metabolized by hepatic lipase into LDL, which retains apo B-100. the products of VLDL and IDL metabolism, are the most cholesterol-rich of all lipoproteins. About 40 to 60% of all LDL are cleared by the liver in a process mediated by apo B and hepatic LDL receptors. The rest are taken up by either hepatic LDL or nonhepatic non-LDL (scavenger) receptors. Hepatic LDL receptors are down-regulated by delivery of cholesterol to the liver by chylomicrons and by increased dietary saturated fat; they can be up-regulated by decreased dietary fat and cholesterol. Nonhepatic scavenger receptors, most notably on macrophages, take up excess LDL that has not been processed by hepatic receptors. Monocytes migrate into the subendothelial space and become macrophages; these macrophages then take up oxidized LDL and form foam cells within Pathophysiology . The size of LDL particles varies from large and buoyant to small and dense. Small, dense LDL is especially rich in cholesterol esters and is associated with metabolic disturbances such as hypertriglyceridemia andinsulinresistance. High-density lipoproteins (HDL)are initially cholesterol-free lipoproteins that are synthesized in both enterocytes and the liver. HDL metabolism is complex, but one role of HDL is to obtain cholesterol from peripheral tissues and other lipoproteins and transport it to where it is needed most—other cells, other lipoproteins (using cholesteryl ester transfer protein [CETP]), and the liver (for clearance). Its overall effect is anti-atherogenic. Efflux of free cholesterol from cells is mediated by ATP-binding cassette transporter A1 (ABCA1), which combines with apoprotein A-I (apo A-I) to produce nascent HDL. Free cholesterol in nascent HDL is then esterified by the enzymelecithin-cholesterol acyl transferase (LCAT), producing mature HDL. Plasma HDL levels may not completely represent reverse cholesterol transport, and the protective effects of higher HDL levels may also be due to anti-oxidant and anti-inflammatory properties. and is thought to competitively inhibit fibrinolysis and thus predispose to thrombus formation. Lp(a) may also directly promote Atherosclerosis . The metabolic pathways of Lp(a) production and clearance are not well characterized, but levels increase in patients with 