Fig. 32.5 ). The initial and rate-limiting step is addition of a hydroxyl group to the 7 position of the steroid nucleus by the enzyme cholesterol 7α-hydroxylase. The side chain of the product of this reaction is then shortened and a carboxylic acid function added by C27 dehydroxylase to yield chenodeoxycholic acid, a dihydroxy bile acid. Alternatively the product is further hydroxylated at the 12 position and then acted on by C27 dehydroxylase to yield cholic acid, a trihydroxy bile acid. Bile acid synthesis can be up-or downregulated depending on the body’s requirements (Fig.
32.6 ). For example, if bile acid levels are reduced in the blood flowing to the liver, synthesis can be increased up to 10-fold. Conversely, feeding of bile acids profoundly suppresses new synthesis of bile acids by hepatocytes. The mechanisms underlying these changes in bile acid synthesis relate to changes in expression of the enzymes involved. Bile acids activate a variety of cell surface and nuclear receptors in hepatocytes, leading ultimately to activation of specific transcription factors that regulate enzyme abundance.
Chenodeoxycholic acid and cholic acid are defined as primary bile acids because they are synthesized by the hepatocyte (see
Fig. 32.5 ). However, each can be metabolized in the colonic lumen by bacterial enzymes to yield ursodeoxycholic and deoxycholic acid, respectively. Chenodeoxycholic acid is also converted by bacterial enzymes to form lithocholic acid, which is relatively cytotoxic. Collectively these three products of bacterial metabolism are referred to as secondary bile acids. One additional important biochemical modification occurs for both primary and secondary bile acids in the hepatocyte (see
Fig.
32.5 ). These molecules are conjugated with either glycine or taurine, which significantly depresses their pKa. The result is that conjugated bile acids are almost totally ionized at the pH prevailing in the small intestinal lumen and thus cannot passively traverse cell membranes. Consequently the conjugated bile acids are retained in the intestinal lumen until they are actively absorbed in the terminal ileum via the apical sodium-dependent bile salt transporter (asbt). Conjugated bile acids that escape this uptake step are deconjugated by bacterial enzymes in the colon, and the resulting unconjugated forms are passively reabsorbed across the colonic epithelium because they are no longer charged.
Hepatic Aspects of Enterohepatic Circulation of Bile Acids
Bile acids assist in digestion and absorption of lipids by acting as detergents rather than enzymes, and thus a significant mass of these molecules is required to solubilize all dietary lipids. Via the enterohepatic circulation, actively reabsorbed conjugated bile acids travel through the portal blood back to the hepatocyte, where they are efficiently taken up by basolateral transporters that may be Na+ dependent or independent (see
Table 32.1 ). Similarly, bile acids that are deconjugated in the colon also return to the hepatocyte, where they are reconjugated to be secreted into bile. In this way a pool of circulating primary and secondary