Cholesterol 7 alpha-hydroxylase: evidence for transcriptional regulation by cholesterol or metabolic products of cholesterol in the rat.
Cholesterol 7 alpha-hydroxylase, the rate-determining enzyme in the bile acid biosynthesis pathway, is regulated in a negative feedback manner by hydrophobic bile salts returning to the liver via the portal circulation. The role of cholesterol in the regulation of cholesterol 7 alpha-hydroxylase and the interrelationship between the cholesterol and bile acid biosynthesis pathways remain controversial. The objective of the present study was to define the role of cholesterol in the regulation of cholesterol 7 alpha-hydroxylase and determine the molecular level of its control. In order to avoid intestinal or intravenous administration of cholesterol, we manipulated the flow of cholesterol within the hepatocytes by decreasing cholesterol synthesis with lovastatin in bile fistula rats (bile acid synthesis is up-regulated), or by increasing cholesterol supply by administering mevalonate, a precursor of cholesterol, to rats with intact enterohepatic circulation (bile acid synthesis is normal). In the first series of studies, lovastatin was administered as a single intravenous bolus (10 mg/kg) to rats with chronic bile fistula and to rats with intact enterohepatic circulation (cholesterol and bile acid synthesis is normal). Three hours after lovastatin administration, cholesterol 7 alpha-hydroxylase specific activity, enzyme mass, mRNA, and gene transcriptional activity were decreased by 35%, 32%, 56%, and 34%, respectively, in rats with chronic bile fistula. In rats with intact enterohepatic circulation, lovastatin administration resulted in a similar decrease (34%) of cholesterol 7 alpha-hydroxylase specific activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Jones
M P
MP
Department of Medicine (Division of Gastroenterology), Medical College of Virginia, Richmond 23298.
Pandak
W M
WM
Heuman
D M
DM
Chiang
J Y
JY
Hylemon
P B
PB
Vlahcevic
Z R
ZR
D000818:Animals; D001658:Biliary Fistula; D002784:Cholesterol / Q000378:metabolism / Q000502:physiology*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D004764:Enterohepatic Circulation; D015971:Gene Expression Regulation, Enzymologic; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic
D002784:Cholesterol; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase; D008798:Mevalonic Acid