The Continuing Importance of Bile Acids in Liver and Intestinal Disease

Abstract

Bile acids, the water-soluble, amphipathic end products of cholesterol metabolism, are involved in liver, biliary, and intestinal disease. Formed in the liver, bile acids are absorbed actively from the small intestine, with each molecule undergoing multiple enterohepatic circulations before being excreted. After their synthesis from cholesterol, bile acids are conjugated with glycine or taurine, a process that makes them impermeable to cell membranes and permits high concentrations to persist in bile and intestinal content. The relation between the chemical structure and the multiple physiological functions of bile acids is reviewed. Bile acids induce biliary lipid secretion and solubilize cholesterol in bile, promoting its elimination. In the small intestine, bile acids solubilize dietary lipids promoting their absorption. Bile acids are cytotoxic when present in abnormally high concentrations. This may occur intracellularly, as occurs in the hepatocyte in cholestasis, or extracellularly, as occurs in the colon in patients with bile acid malabsorption. Disturbances in bile acid metabolism can be caused by (1) defective biosynthesis from cholesterol or defective conjugation, (2) defective membrane transport in the hepatocyte or ileal enterocyte, (3) defective transport between organs or biliary diversion, and (4) increased bacterial degradation during enterohepatic cycling. Bile acid therapy involves bile acid replacement in deficiency states or bile acid displacement by ursodeoxycholic acid, a noncytotoxic bile acid. In cholestatic liver disease, administration of ursodeoxycholic acid decreases hepatocyte injury by retained bile acids, improving liver tests, and slowing disease progression. Bile acid malabsorption may lead to high concentrations of bile acids in the colon and impaired colonic mucosal function; bile acid sequestrants provide symptomatic benefit for diarrhea. A knowledge of bile acid physiology and the perturbations of bile acid metabolism in liver and digestive disease should be useful for the internist.

Inflammatory Bowel Disease Alters Intestinal Bile Acid Transporter Expression

“…Due to efficient conservation within the enterohepatic circulation, only small amounts of BA escape reabsorption in the ileum and colon and must be replaced by hepatic de novo synthesis (Hofmann, 1999;Kullak-Ublick et al, 2004). BA uptake into the enterocyte occurs principally in the terminal ileum via the apical sodium dependent BA transporter (ASBT; SLC10A1 gene).…”

“…BA uptake into the enterocyte occurs principally in the terminal ileum via the apical sodium dependent BA transporter (ASBT; SLC10A1 gene). Secondary BA produced by bacteria in the colon enter the colonic enterocyte exclusively by passive diffusion (Hofmann, 1999). Several exporter proteins at enterocyte basolateral and apical membranes pump both primary and secondary BA into the blood or the gut lumen (see Fig.…”

Extending in vitro digestion models to specific human populations: Perspectives, practical tools and bio-relevant information

“…Every day, the human liver produces about 0.6e1.0 L of bile, which are stored in the gallbladder (Seeley et al, 1992). Bile acids are steroid acids composed mainly from taurocholic acid, glycocholic acid, taurochenodeoxycholic acid and glycochenodeoxycholic acid which are equal in concentration (Hofmann, 1999). In addition to enzymes delivered into the lumen, enzymes located in the epithelial brush border contribute to the further digestion of food.…”

Apical Sodium Dependent Bile Acid Transporter (ASBT, SLC10A2): A Potential Prodrug Target

“…The principal bile acids in human bile are mainly conjugated cholic acid and chenodeoxycholic acid 16 . Very small amounts of deoxycholate and ursodeoxycholate conjugates, and trace lithocholate conjugates, are also present.…”

“…ASBT and NTCP serve to transport bile acids from the small intestine into portal circulation and from the portal circulation into the hepatocyte. The bile acid pool in humans is about 3-5 g, resulting in a turnover of 12-18 g of bile acid each day 16 . In spite of this repeated cycling, the loss of bile in the feces is less than 0.5 g per day, reflecting the tremendous capacity and efficiency of hASBT 19 .…”