Lipid metabolism

Lipids are carried in plasma by lipoproteins, which have an external hydrophilic region containing proteins, phospholipids, and nonsterified cholesterol, and an internal hydrophobic core, containing triacylglycerols (TAGs) and cholesterol esters. Based on their density, different lipoprotein groups can be distinguished in blood. (1) Chylomicrons, which contain mainly TAGs synthesized in the intestinal mucosa from fatty acids (FAs) and monoacylglycerols from the diet. A lipoprotein lipase (LpL) in capillary endothelial cells hydrolyze TAG. The freed FA enter the cells, where they are oxidized (muscle) or stored (adipose tissue). The chylomicron remnants, reduced to its protein component (apolipoprotein B-48, or apo-48) bind to liver receptors and are internalized and cleared from circulation. (2) Very low density lipoproteins (VLDLs) are synthesized in hepatocytes. They are rich in TAG and contains protein B-100. In the capillaries, TAGs are hydrolyzed by LpL and they exchange TAG for cholesterol esters from high-density lipoproteins (HDLs). VLDLs are converted to intermediate density lipoproteins (IDLs). TAGs are hydrolyzed by liver lipase, apo E returns to HDL. Hepatocytes remove more than 50% of IDL from the circulation. The rest are the low density density lipoproteins (LDLs), rich in Chol. All cells have receptors that bind B-100 and internalize LDL composed of apos B-100 and E, Chol, mostly CholE, and low proportion of TAG. (3) HDLs are synthesized in the liver and intestine and contain apo A, C, and E, lecithin-cholesterol acyltransferase (LCAT) and phospholipids. In blood, HDL donates apo C and E to VLDL and chylomicrons. In extrahepatic tissues, HDL binds to the capillary endothelium and receives cholesterol from the cells, which is esterified by LCAT and transferred to VLDL and chylomicrons (reverse cholesterol transport). Remnants of these particles are taken up by the liver. Fat metabolism starts with the hydrolysis of TAG into glycerol (Glyc) and FA, by the action of intracellular lipase and LpL. Glycerol is converted into glyceraldehyde-3-P that can be directed to glycolysis or gluconeogenesis. FAs are catabolyzed in mitochondria by β-oxidation. β-oxidation follows a series of oxidative steps and the release of acyl-CoA. Ketogenesis produces ketone bodies from acetoacetate, 3-OH butyrate, and acetone. Muscle, heart, and other tissues are capable of activating acetoacetate and can use ketone bodies as fuel; the liver cannot. FA biosynthesis takes place from acetyl-CoA (generated mainly by degradation of glucose and amino acid carbon chains) by the FA synthase multienzyme system. Essential polyunsaturated FA cannot be synthesized, they must be obtained from the diet. Eicosanoids (prostaglandins, thromboxanes, and leukotrienes) are synthesized from arachidonic acid and catalyzed by cyclo-oxigenase. Biosynthesis of triacylglycerols (TAG) starts with the activation of glycerol to glycerol-3-P and FAs to acyl-CoA. Glycerol-3-phosphate is esterified at carbons 1 and 2 by two acyl groups transferred from acyl-CoA to form 1,2-diacylglycerolphosphate, also called phosphatidic acid. A new acyl-CoA molecule transfers another acyl to 1,2-diacylglycerol and triacylglycerol is produced. Phospholipids in higher animals are synthesized from phosphatidic acid. Cholesterol synthesis comprises three stages: acetate to mevalonate, mevalonate to squalene, and squalene to Chol. It is removed from plasma by LDL receptors in all cells. Bile acids and steroid hormones are synthesized from cholesterol.