描述
Bile acids are made in the liver by the cytochrome P450-mediated oxidation of cholesterol. They are conjugated with taurine or the amino acid glycine, or with a sulfate or a glucuronide, and are then stored in the gallbladder. Upon eating a meal, the contents of the gallbladder are secreted into the intestine, where bile acids serve the purpose of emulsifying dietary fats. Bile acids serve other functions, including eliminating cholesterol from the body, driving the flow of bile to eliminate catabolites from the liver, emulsifying lipids and fat soluble vitamins in the intestine, and aiding in the reduction of the bacteria flora found in the small intestine and biliary tract. Bile acids formed by synthesis in the liver are termed "primary" bile acids, and those made by bacteria are termed "secondary" bile acids. In the liver, synthesis of bile acids and bile salts is initiated with the conversion of cholesterol esters (from circulating lipoprotein particles) to cholesterol, then to 7alpha-hydroxycholesterol then to 4-cholesten-7alpha-ol-3-one. The pathway then branches: hydroxylation of 4-cholesten-7alpha-ol-3-one to 4-cholesten-7alpha, 12alpha-diol-3-one leads ultimately to the formation of cholate, while its reduction to 5beta-cholestan-7alpha-ol-3-one leads to the formation of chenodeoxycholate. Chenodeoxycholate has two hydroxyl groups at positions 3-alpha and 7-alpha and is a key bile acid. Its chief drawback lies in the ability of intestinal bacteria to remove the 7-alpha hydroxyl group via dehydroxylation. The resulting bile acid has only a 3-alpha hydroxyl group and is termed lithocholic acid. To avoid the problems associated with the production of lithocholic acid, most mammals add a third hydroxyl group at the 12 position to chenodeoxycholic acid to create cholic acid. In this manner, the subsequent removal of the 7-alpha hydroxyl group by intestinal bacteria will result in a less toxic, still functional dihydroxy bile acid. In the intestine, cholic acid is dehydroxylated to form the dihydroxy bile acid deoxycholic acid. Prior to secretion by the liver, they are conjugated with either the amino acid glycine or taurine through conversion to a Coenzyme A derivative and subsequent conjugation. In the body, glycocholate, taurocholate, glycochenodeoxycholate, and taurochenodeoxycholate are released from hepatocytes into the bile and ultimately into the lumen of the small intestine, where they function as detergents to solubilize dietary fats. Conjugation increases water solubility, preventing passive re-absorption once secreted into the small intestine. As a result, the concentration of bile acids in the small intestine can stay high enough to form micelles and solubilize lipids. Bile acids, in particular chenodeoxycholic acid (CDCA) and cholic acid (CA), can regulate the expression of genes involved in their synthesis, thereby, creating a feed-back loop. The elucidation of this regulatory pathway came about as a consequence of the isolation of a class of receptors called the farnesoid X receptors, FXRs. The FXRs belong to the superfamily of nuclear receptors that includes the steroid/thyroid hormone receptor family as well as the liver X receptors (LXRs), retinoid X receptors (RXRs), and the peroxisome proliferator-activated receptors (PPARs). The FXR genes are expressed at highest levels in the intestine and liver.