Regulation of bile acid synthesis. I. Effects of conjugated ursodeoxycholate and cholate on bile acid synthesis in chronic bile fistula rat

Authors

  • Douglas M. Heuman,

    1. Division of Gastroenterology, McGuire Veterans Administration Medical Center and Departments of Medicine and Microbiology, Medical College of Virginia, Richmond, Virginia 23249
    Search for more papers by this author
  • Carmen R. Hernandez,

    1. Division of Gastroenterology, McGuire Veterans Administration Medical Center and Departments of Medicine and Microbiology, Medical College of Virginia, Richmond, Virginia 23249
    Search for more papers by this author
  • Philip B. Hylemon,

    1. Division of Gastroenterology, McGuire Veterans Administration Medical Center and Departments of Medicine and Microbiology, Medical College of Virginia, Richmond, Virginia 23249
    Search for more papers by this author
  • William M. Kubaska,

    1. Division of Gastroenterology, McGuire Veterans Administration Medical Center and Departments of Medicine and Microbiology, Medical College of Virginia, Richmond, Virginia 23249
    Search for more papers by this author
  • Constance Hartman,

    1. Division of Gastroenterology, McGuire Veterans Administration Medical Center and Departments of Medicine and Microbiology, Medical College of Virginia, Richmond, Virginia 23249
    Search for more papers by this author
  • Z. Reno Vlahcevic M.D.

    Corresponding author
    1. Division of Gastroenterology, McGuire Veterans Administration Medical Center and Departments of Medicine and Microbiology, Medical College of Virginia, Richmond, Virginia 23249
    • Gastroenterology Section (111N), McGuire Veterans Administration Medical Center, 1200 East Broad Rock Road, Richmond, Virginia 23249
    Search for more papers by this author

Abstract

Bile acid synthesis is thought to be regulated by a negative feedback mechanism which is presumably dependent upon the flux of bile acids in the enterohepatic circulation. To characterize further the role of bile acids in regulation of bile acid synthesis, we have administered pure taurine or glycine conjugates of ursodeoxycholic acid or cholic acid to chronic bile fistula rats by continuous intraduodenal infusion, thus simulating restoration of the enterohepatic circulation. The effects of these bile salt infusions on bile acid synthesis, biliary cholesterol and phospholipid secretion and on the activities of the hepatic microsomal enzymes cholesterol 7α-hydroxylase and HMG-CoA reductase were evaluated. Because the rate of biliary bile salt secretion in rats with intact exteriorized enterohepatic circulation averaged 27.1 ± 1.4 pinoles per 100 gm rat per hr, infusion rates for bile fistula studies were chosen to match (24 to 36 μmoles per 100 gm rat per hr) or exceed (48 μmoles per 100 gm rat per hr) this physiological flux.

Infusion of tauroursodeoxycholic acid for 48 hr at 24 and 48 μmoles per 100 gm rat per hr failed to suppress cholic acid synthesis. Bile flow and biliary cholesterol and phospholipid secretion exhibited small, dose-dependent increases with tauroursodeoxycholic acid infusions. No suppression of cholesterol 7α-hydroxylase or HMG-CoA reductase activity was observed. By contrast, taurocholic acid inhibited synthesis of chenodeoxycholate and its metabolites α- and β-muricholate by 10% (NS), 66% (p < 0.05) and 75% (p < 0.05) at infusion rates of 24, 36 and 48 μmoles per 100 gm rat per hr, respectively. Taurocholic acid infusion at 24, 36 and 48 μmoles per 100 gm rat per hr resulted in 30, 34 and 32% suppression of cholesterol 7α-hydroxylase activity, respectively. After taurocholic acid infusion, HMG-CoA reductase activity declined in parallel with cholesterol 7α-hydroxylase. Taurocholic acid caused a pronounced, dose-dependent increase in bile flow and in biliary secretion of cholesterol and phospholipid. Biliary cholesterol secretion increased 166, 152 and 211%, respectively, with taurocholic acid infusion rates of 24, 36 and 48 μmoles per 100 gm rat per hr. With the same infusion rates, phospholipid secretion increased by 128, 267 and 510%. Neither tauroursodeoxycholic acid nor taurocholic acid caused a significant change in total microsomal cholesterol content.

We conclude that the potency of different bile acids as mediators of bile acid biofeedback, promoters of biliary cholesterol and phospholipid secretion, and suppressors of cholesterol 7α-hydroxylase and HMG-CoA reductase, varies with their structure, possibly as a function of their monomeric hydrophobicity. The existence of an apparent inverse relationship between bile acid synthesis and biliary lipid secretion suggests that the activities of the key hepatic microsomal enzymes regulating cholesterol and bile acid synthesis may be controlled indirectly via changes in the lipid composition or fluidity of the microsomal membranes.

Ancillary