Regulation of hepatic sterol metabolism in the rat. Parallel regulation of activity and mRNA for 7 alpha-hydroxylase but not 3-hydroxy-3-methylglutaryl-coenzyme A reductase or low density lipoprotein receptor.
In vivo regulation of hepatic sterol metabolism was examined in the rat. Sodium cholate markedly suppressed hepatic 7 alpha-hydroxylase mRNA levels and activity when fed to rats on a low cholesterol diet. Sterol balance was maintained solely by decreasing hepatic cholesterol synthesis. Compensatory mechanisms were inadequate when cholate was fed to rats on a high cholesterol diet and massive amounts of cholesterol accumulated in the liver and plasma. Suppression of bile salt synthesis was not responsible since cholate did not suppress 7 alpha-hydroxylase activity when fed to rats on a high cholesterol diet. Moreover, total hepatic low density lipoprotein receptor activity was not suppressed even though liver cholesteryl ester levels were increased more than 350-fold. Changes in 7 alpha-hydroxylase activity were always accompanied by parallel changes in mRNA, whereas mRNA levels for 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase were reduced by 50% or less, even when cholesterol synthesis was suppressed by 98%. HMG-CoA reductase and low density lipoprotein receptor activities were regulated independently although mRNA levels for these two proteins were coordinately regulated. These findings indicate that 7 alpha-hydroxylase is controlled by mRNA levels, whereas in vivo cholesterol synthesis is predominantly controlled by posttranscriptional regulation of HMG-CoA reductase activity.
Spady
D K
DK
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8887.
Cuthbert
J A
JA
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001647:Bile Acids and Salts / Q000378:metabolism / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D019826:Cholic Acid; D002793:Cholic Acids / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics* / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011973:Receptors, LDL / Q000235:genetics*; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism*
D001647:Bile Acids and Salts; D002791:Cholesterol, Dietary; D002793:Cholic Acids; D012333:RNA, Messenger; D011973:Receptors, LDL; D013261:Sterols; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C029009:steroid hormone 7-alpha-hydroxylase; D019826:Cholic Acid