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Cholesterol 7 alpha-hydroxylase: evidence for transcriptional regulation by cholesterol or metabolic products of cholesterol in the rat

1993; Elsevier BV; Volume: 34; Issue: 6 Linguagem: Inglês

10.1016/s0022-2275(20)39675-9

1539-7262

MP Jones, WM Pandak, DM Heuman, JY Chiang, PB Hylemon, Vlahcevic Zr,

Cancer, Lipids, and Metabolism

Cholesterol 7a-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 7a-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 7ahydroxylase 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 7a-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 7a-hydroxylase specific activity.In the second group of experiments, rats with intact enterohepatic circulation were administered a 180 pM bolus of mevalonate followed by a continuous infusion of I80 @bVh for 1.5, 3, 4.5, and 24 h prior to being killed.CoKtinuoUs infusion of mevalonate increased cholesterol 7 ahydroxylase specific activity, mRNA levels, and transcriptional activity by an average of 2-to %fold at all time intervals.I1p We conclude that under circumstances in which cholesterol is present in excess, cholesterol 7a-hydroxylase transcriptional activity is up-regulated and removal of cholesterol from the hepatocytes is facilitated by an increase of bile acid synthesis.When cholesterol availability is decreased, cholesterol 7a- hydroxylase transcriptional activity is down-regulated leading to a decreased elimination of cholesterol via bile acid synthesis.In both instances, hepatic cholesterol homeostasis is effectively maintained.-Jones,M.