S. Shefer et al., REGULATION OF BILE-ACID SYNTHESIS BY DEOXYCHOLIC-ACID IN THE RAT - DIFFERENT EFFECTS ON CHOLESTEROL 7-ALPHA-HYDROXYLASE AND STEROL 27-HYDROXYLASE, Hepatology, 22(4), 1995, pp. 1215-1221
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.