Transcriptional regulation of hepatic sterol 27-hydroxylase by bile acids.
The study objective was to determine whether and to what extent sterol 27-hydroxylase, the initial step in the "acidic" pathway of bile acid biosynthesis, is regulated by bile acids. Rats were fed diets supplemented with cholestyramine (CT, 5%), cholate (CA, 1%), chenodeoxycholate (CDCA, 1%), or deoxycholate (DCA, 0.25%). When compared with paired controls, sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase specific activities increased after CT administration by 188 +/- 20% (P < 0.05) and 415 +/- 36% (P < 0.01), respectively. Similarly, mRNA levels increased by 159 +/- 14% (P < 0.05) and 311 +/- 106% (P < 0.05), respectively. Feeding CA, CDCA, or DCA decreased sterol 27-hydroxylase specific activity to 57 +/- 6, 61 +/- 8, and 74 +/- 8% of controls, respectively (P < 0.05). By comparison, the specific activity of cholesterol 7 alpha-hydroxylase decreased to 46 +/- 7 , 32 +/- 10, and 26 +/- 8% (P = 0.001). mRNA levels and transcriptional activities for sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase transcriptional activity were changed to the same extent as the specific activities after CT or bile acid feeding. We conclude that sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase are subject to negative feedback regulation by hydrophobic bile acids at the level of transcription. However, the responses of sterol 27-hydroxylase to manipulation of the bile acid pool are less prominent than those of cholesterol 7 alpha-hydroxylase. During the diurnal cycle the specific activities of sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase changed in tandem, suggesting that both may be under control of glucocorticoids.
Vlahcevic
Z R
ZR
Section of Gastroenterology, McGuire Veterans Affairs Medical Center, Richmond, Virginia, USA.
Jairath
S K
SK
Heuman
D M
DM
Stravitz
R T
RT
Hylemon
P B
PB
Avadhani
N G
NG
Pandak
W M
WM
D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology / Q000502:physiology*; D053493:Cholestanetriol 26-Monooxygenase; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D002792:Cholestyramine Resin / Q000494:pharmacology; D002940:Circadian Rhythm; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D006706:Homeostasis; D008099:Liver / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*
D001647:Bile Acids and Salts; D065607:Cytochrome P-450 Enzyme Inhibitors; D012333:RNA, Messenger; D002792:Cholestyramine Resin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D002790:Cholesterol 7-alpha-Hydroxylase; D053493:Cholestanetriol 26-Monooxygenase