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 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 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 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 7 alpha-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 7 alpha-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 7 alpha-hydroxylase in rats fed 1% deoxycholic acid. In contrast, 0.4% deoxycholic acid decreased HMG-CoA reductase mRNA levels 76%, and cholesterol 7 alpha-hydroxylase mRNA levels 82%. Ursodeoxycholic acid alone did not affect HMG-CoA reductase or cholesterol 7 alpha-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.(ABSTRACT TRUNCATED AT 250 WORDS)
Shefer
S
S
Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, USA.
Kren
B T
BT
Salen
G
G
Steer
C J
CJ
Nguyen
L B
LB
Chen
T
T
Tint
G S
GS
Batta
A K
AK
D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000096:biosynthesis* / Q000097:blood; D002467:Cell Nucleus / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury; D002756:Cholagogues and Choleretics / Q000008:administration & dosage / Q000633:toxicity*; D053493:Cholestanetriol 26-Monooxygenase; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000633:toxicity*; D004032:Diet; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000201:enzymology / Q000517:prevention & control; D008297:Male; D009336:Necrosis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013250:Steroid Hydroxylases / Q000378:metabolism*; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage
D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D012333:RNA, Messenger; D003840:Deoxycholic Acid; D014580:Ursodeoxycholic Acid; D003577:Cytochrome P-450 Enzyme System; D006903:Hydroxymethylglutaryl CoA Reductases; D013250:Steroid Hydroxylases; D002790:Cholesterol 7-alpha-Hydroxylase; D053493:Cholestanetriol 26-Monooxygenase