Regulation of bile acid synthesis by deoxycholic acid in the rat: Different effects on cholesterol 7α-hydroxylase and sterol 27-hydroxylase

✍ Scribed by Sarah Shefer; Betsy T. Kren; Gerald Salen; Clifford J. Steer; Lien B. Nguyen; Thomas Chen; G. Stephen Tint; Ashok K. Batta

• Publisher: John Wiley and Sons
• Year: 1995
• Tongue: English
• Weight: 982 KB
• Volume: 22
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.1840220429

✦ Synopsis

We examined the effects of feeding deoxycholic acid (1% and 0.4% of diet), alone and in combination with ursodeoxycholic acid, on serum and biliary bile acid concentrations, hepatic morphology, and the activities and steady-state messenger RNA (mRNA) levels of HMG-CoA reductase and cholesterol 7a-hydroxylase in the rat. Feeding 1% deoxycholic acid increased serum bile acid concentrations (cholestasis), produced portal triad inflammation, bile duct proliferation, and severe hepatocyte necrosis with nuclear pleomorphism. Hepatic damage was prevented when ursodeoxycholic acid (1%) was combined with the deoxycholic acid (l%), or when deoxycholic acid intake was reduced to 0.4%. HMG-CoA reductase and cholesterol 7a-hydroxylase activities were markedly inhibited (-56% and 4 5 % , respectively) with either 1% or 0.4% deoxycholic acid. Ursodeoxycholic acid alone produced an insignificant decline in HMG-CoA reductase and cholesterol 7a-hydroxylase activities, and when combined with 1% deoxycholic acid did not lessen the inhibitory effect of the latter. Steadystate mRNA levels increased 20-fold for HMG-CoA reductase and 53-fold for cholesterol 7a-hydroxylase in rats fed 1% deoxycholic acid. In contrast, 0.4% deoxycholic acid decreased HMG-CoA reductase mRNA levels 76%, and cholesterol 7ru-hydroxylase mRNA levels 82%. Ursodeoxycholic acid alone did not affect HMG-CoA reductase or cholesterol 7a-hydroxylase steady-state mRNA levels. Steady-state mRNA levels and activities of sterol 27-hydroxylase, a key enzyme in the alternative acidic pathway of bile acid synthesis, did not change with either high or low doses of deoxycholic acid. In conclusion, 1% deoxycholic acid induced hepatocyte destruction and regeneration associated with increased mRNA levels for Abbreviations: mRNA, messenger RNA, SDS, sodium dodecyl sulfate.