Regulation of sterol 12alpha-hydroxylase and cholic acid biosynthesis in the rat.
OBJECTIVE
Sterol 12alpha-hydroxylase (CYP8b1) is required for the biosynthesis of cholic acid (CA) and hence helps determine the ratio of CA to chenodeoxycholic acid (CDCA) in bile. This study examined the in vivo regulation of CYP8b1 in the rat by bile acids, cholesterol, and thyroxine.


METHODS
The specific activities (SAs), messenger RNA (mRNA) levels, and transcriptional activities of CYP8b1 were determined in intact rats and rats with biliary diversion.


RESULTS
CA, CDCA, and deoxycholic acid (DCA), fed as a supplement to the diet, down-regulated CYP8b1 SAs by 99% +/- 0%, 72% +/- 10%, and 98% +/- 1%, respectively. Under these same conditions, mRNA levels decreased by 93% +/- 7%, 60% +/- 11%, and 93% +/- 4%, respectively. Intraduodenal infusion of taurocholate (36 micromol/h. 100 g rat(-1)) decreased SAs and mRNA levels by 63% +/- 8% and 74% +/- 8%, respectively. Ursodeoxycholic acid (UDC) and hyocholic acid (HC) feeding increased CYP8b1 SAs by 119% +/- 21% and 65% +/- 18%, respectively. CA feeding decreased CYP8b1 transcriptional activity by 72%. Complete biliary diversion increased CYP8b1 SAs and mRNA levels by 150% +/- 30% and 287% +/- 51%, respectively. Cholesterol feeding decreased CYP8b1 mRNA by 39% +/- 8%. In intact rats, a single injection of thyroid hormone eliminated CYP8b1 activity.


CONCLUSIONS
CYP8b1 is transcriptionally down-regulated by hydrophobic but not hydrophilic bile acids. Cholesterol feeding and a single thyroid hormone injection repressed CYP8b1 in the face of induction of cholesterol 7alpha-hydroxylase (CYP7a1 by the new nomenclature) SAs. These results suggest that cholesterol, thyroid hormone, and hydrophobic bile acids are important regulators of CYP8b1 and consequently of the bile acid pool composition.
Vlahcevic
Z R
ZR
Division of Gastroenterology, McGuire Veterans Administration Medical Center, Virginia Commonwealth University, Richmond, Virginia 23249, USA.
Eggertsen
G
G
Björkhem
I
I
Hylemon
P B
PB
Redford
K
K
Pandak
W M
WM
D000818:Animals; D001646:Bile / Q000502:physiology; D001647:Bile Acids and Salts / Q000008:administration & dosage / Q000494:pharmacology; D002784:Cholesterol / Q000008:administration & dosage / Q000494:pharmacology; D019826:Cholic Acid / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004032:Diet; D015536:Down-Regulation; D008297:Male; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013253:Steroid 12-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D013974:Thyroxine / Q000008:administration & dosage / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D001647:Bile Acids and Salts; D065607:Cytochrome P-450 Enzyme Inhibitors; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D013250:Steroid Hydroxylases; D013253:Steroid 12-alpha-Hydroxylase; D019826:Cholic Acid; D013974:Thyroxine