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

Abstract

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 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 (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-CoAreductase 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.