Cholesterol is a hydrophobic compound, with a single hydroxyl group located at carbon 3 of the A ring, to which a fatty acid (FA) can be attached, producing an even more hydrophobic cholesteryl ester. Cholesterol is synthesized by virtually all human tissues, although primarily by the liver, intestine, adrenal cortex, and reproductive tissues (Fig. 18.29). All the carbon atoms are provided by acetyl coenzyme A (CoA), and nicotinamide adenine dinucleotide phosphate provides the reducing equivalents. The pathway is driven by hydrolysis of the high-energy thioester bond of acetyl CoA and the terminal phosphate bond of ATP. Synthesis requires enzymes of the cytosol, smooth endoplasmic reticulum (SER), and peroxisomes. The rate-limiting and regulated step in cholesterol synthesis is catalyzed by the SER-membrane protein hydroxymethylglutaryl coenzyme A (HMG CoA) reductase, which produces mevalonate from HMG CoA. The enzyme is regulated by a number of mechanisms: 1) increased expression of the reductase gene when cholesterol levels are low, via the transcription factor, sterol regulatory element–binding protein-2 (SREBP-2), bound to a sterol regulatory element (SRE), resulting in increased enzyme and, therefore, cholesterol, synthesis; 2) accelerated degradation of the reductase protein when cholesterol levels are high; 3) phosphorylation (causing inactivation of reductase activity) by adenosine monophosphate–activated protein kinase [AMPK] and dephosphorylation (activation) by a phosphoprotein phosphatase; and 4) hormonal regulation by insulin and glucagon. Statins are competitive inhibitors of HMG CoA reductase. These drugs are used to decrease plasma cholesterol in patients with hypercholesterolemia. The ring structure of cholesterol cannot be degraded in humans.
Cholesterol is eliminated from the body either by conversion to bile salts or by secretion into the bile. Bile salts and phosphatidylcholine (PC) are quantitatively the most important organic components of bile. The rate-limiting step in bile acid synthesis is catalyzed by cholesterol-7-αhydroxylase, which is inhibited by bile acids. Before the bile acids leave the liver, they are conjugated to a molecule of either glycine or taurine, producing the conjugated bile salts glycocholic or taurocholic acid and glycochenodeoxycholic or taurochenodeoxycholic acid. Bile salts (deprotonated) are more amphipathic than bile acids (protonated) and, therefore, are more effective emulsifiers of dietary fat. Intestinal bacteria can remove the glycine and taurine as well as a hydroxyl group from the steroid nucleus, producing the secondary bile salts, deoxycholic and lithocholic acids. Bile salts are efficiently reabsorbed (>95%) in the intestinal ileum by a sodium–bile salt cotransporter, returned to the blood, and carried by albumin back to the liver where they are taken up by the hepatic isoform of the cotransporter and reused (enterohepatic circulation, which bile acid sequestrants reduce). If more cholesterol enters the bile than can be solubilized by the available bile salts and PC, cholesterol gallstone disease (cholelithiasis) can occur.