Overview of Lipid Metabolism
Lipids are fats that are either absorbed from food or synthesized by the liver. Triglycerides (TGs) and cholesterol contribute most to disease, although all lipids are physiologically important.
Cholesterol is a ubiquitous constituent of cell membranes, steroids, bile acids, and signaling molecules.
Triglycerides primarily store energy in adipocytes and muscle cells.
Lipoproteins are hydrophilic, spherical structures that possess surface proteins (apoproteins, or apolipoproteins) that are cofactors and ligands for lipid-processing enzymes (see table Major Apoproteins and Enzymes Important to Lipid Metabolism). All lipids are hydrophobic and mostly insoluble in blood, so they require transport within lipoproteins. Lipoproteins are classified by size and density (defined as the ratio of lipid to protein) and are important because high levels of low-density lipoproteins (LDL) and low levels of high-density lipoproteins (HDL) are major risk factors for atherosclerotic heart disease.
Major Apoproteins and Enzymes Important to 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
The remaining about 5% of dietary lipids are
Dietary TGs are digested in the stomach and duodenum into monoglycerides (MGs) and FFAs by gastric lipase, emulsification from 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.
Very-low-density lipoproteins (VLDL) 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 with increases in intrahepatic FFAs, such as occur with high-fat diets and when excess adipose tissue releases FFAs directly into the circulation (eg, in obesity, uncontrolled diabetes mellitus). Apo C-II on the VLDL surface activates endothelial LPL to break down TGs into FFAs and glycerol, which are taken up by cells.
Intermediate-density lipoproteins (IDL) are the product of LPL processing of VLDL and chylomicrons. IDL are cholesterol-rich VLDL and chylomicron remnants that are either cleared by the liver or metabolized by hepatic lipase into LDL, which retains apo B-100.
Low-density lipoproteins (LDL), 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 oxidized circulating LDL not processed by hepatic receptors. Monocytes rich in oxidized LDL migrate into the subendothelial space and become macrophages; these macrophages then take up more oxidized LDL and form foam cells within atherosclerotic plaques.
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 and insulin resistance.
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 enzyme lecithin-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.
Lipoprotein (a) [Lp(a)] is LDL that contains apoprotein (a), characterized by 5 cysteine-rich regions called kringles. One of these regions is homologous with plasminogen and is thought to competitively inhibit fibrinolysis and thus predispose to thrombus formation. The 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 chronic kidney disease, especially in patients on dialysis.