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

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 7α‐hydroxylase in the rat. Feeding 1% deoxycholic acid increased serum bile acid concentrations (cholestasis), produced portal traid inflammation, bile duct proliferation, and severe hepatocyte necrosis with nuclear pleomorphism. Hepatic demage was preventage when ursodeoxycholic acid (1%) was combined with the deoxycholic acid (1%), or when deoxycholic acid intake was reduced to 0.4%. HMG‐CoA reductase and cholesterol 7α‐hydroxylase activities were markedly inhibited (−56% and −55%, respectively) with either 1% or 0.4% deoxycholic acid. Ursodeoxycholic acid alone produced an insignificant decline in HMG‐CoA reductase and cholesterol 7α‐hydroxylase activities, and when combined with 1% deoxycholic acid did not lessen the inhibitory effect of the latter. Steady‐state mRNA levels increased 20‐fold for HMG‐CoA reductase and 53‐fold for cholesterol 7α‐hydroxylase in rats fed 1% deoxycholic acid. In contrast, 0.4% deoxycholic acid decreased HMG‐CoA reductase mRNA levels 76%, and cholesterol 7α‐hydroxylase mRNA levels 82%. Ursodeoxycholic acid alone did not affect HMG‐CoA reductase or cholesterol 7α‐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 HMG‐CoA reductase and cholesterol 7α‐hydroxylase, but significantly suppressed both enzyme activities. Thus, high‐dose deoxycholic acid uncouples HMG‐CoA reductase and cholesterol 7α‐hydroxylase mRNA levels from enzyme function. In contrast, lower‐dose deoxycholic acid (0.4%) inhibited both activities and mRNA levels of HMG‐CoA reductase and cholesterol 7α‐hydroxylase. Adding 1% ursodeoxycholic acid to 1% deoxycholic acid prevented the rise in mRNA levels but did not lessen the inhibitory effect of the latter. This inhibition occurred without change in hepatic histology, which suggests a regulatory role for deoxycholic acid that is independent of liver damage. Conversely, sterol 27‐hydroxylase activity and mRNA levels are not affected by deoxycholic acid treatments. (HEPATOLOGY 1995; 22:1215–1221.).