REGULATION OF BILE-ACID SYNTHESIS BY DEOXYCHOLIC-ACID IN THE RAT - DIFFERENT EFFECTS ON CHOLESTEROL 7-ALPHA-HYDROXYLASE AND STEROL 27-HYDROXYLASE

We examined the effects of feeding deoxycholic acid (1% and 0.4% of di et), alone and in combination with ursodeoxycholic acid, on serum and biliary bile acid concentrations, hepatic morphology, and the activiti es and steady-state messenger RNA (mRNA) levels of HMG-CoA reductase a nd cholesterol 7 alpha-hydroxylase in the rat, Feeding 1% deoxycholic acid increased serum bile acid concentrations (cholestasis), produced portal triad inflammation, bile duct proliferation, and severe hepatoc yte necrosis with nuclear pleomorphism. Hepatic damage was prevented w hen ursodeoxycholic acid (1%) was combined with the deoxycholic acid ( 1%), or when deoxycholic acid intake was reduced to 0.4%, HMG-CoA redu ctase and cholesterol 7 alpha-hydroxylase activities were markedly inh ibited (-56% and -55%, respectively) with either 1% or 0.4% deoxycholi c acid. Ursodeoxycholic acid alone produced an insignificant decline i n HMG-CoA reductase and cholesterol 7 alpha-hydroxylase activities, an d 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 7 alpha-hydroxylase in r ats fed 1% deoxycholic acid. In contrast, 0.4% deoxycholic acid decrea sed HMG-CoA reductase mRNA levels 76%, and cholesterol 7 alpha-hydroxy lase mRNA levels 82%. Ursodeoxycholic acid alone did not affect HMG-Co A reductase or cholesterol 7 alpha-hydroxylase steady-state mRNA level s, 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 c onclusion, 1% deoxycholic acid induced hepatocyte destruction and rege neration associated with increased mRNA levels for HMG-CoA reductase a nd cholesterol 7 alpha-hydroxylase, but significantly suppressed both enzyme activities. Thus, high-dose deoxycholic acid uncouples HMG-CoA reductase and cholesterol 7 alpha-hydroxylase mRNA levels from enzyme function. In contrast, lower-dose deoxycholic acid (0.4%) inhibited bo th activities and mRNA levels of HMG-CoA reductase and cholesterol 7 a lpha-hydroxylase. Adding 1% ursodeoxycholic acid to 1% deoxycholic aci d prevented the rise in mRNA levels but did not lessen the inhibitory effect of the latter. This inhibition occurred without change in hepat ic histology, which suggests a regulatory role for deoxycholic acid th at is independent of liver damage, Conversely, sterol 27-hydroxylase a ctivity and mRNA levels are not affected by deoxycholic acid treatment s.