Journal of Lipid Research, Vol 31, 79-90, Copyright © 1990 by Lipid Research, Inc.

ARTICLES

Regulation of bile acid synthesis. IV. Interrelationship between cholesterol and bile acid biosynthesis pathways

WM Pandak, DM Heuman, PB Hylemon and ZR Vlahcevic
Department of Medicine, Medical College of Virginia, Richmond 23298.

Under most experimental conditions, the activities of 3-hydroxy-3- methylglutaryl coenzyme A (HMG-CoA reductase) and cholesterol 7 alpha- hydroxylase, change together in parallel directions. It has been suggested that newly synthesized cholesterol may be the preferred substrate for cholesterol 7 alpha-hydroxylase, which may account for the observed synchronous behavior of the two enzymes. To test this hypothesis, mevinolinic acid, a potent competitive inhibitor of HMG-CoA reductase, was administered as a single intravenous bolus (10 mg/kg) to rats with a chronic bile fistula. Bile acid synthesis was determined following inhibition of HMG-CoA reductase by mevinolinic acid over a 27- h time course and specific activities of HMG-CoA reductase and cholesterol 7 alpha-hydroxylase were determined in liver microsomes. At 3, 6, and 27 h after a bolus dose of mevinolinic acid, bile acid synthesis was reduced by 54 +/- 5%, 42 +/- 8%, and 23 +/- 13%, respectively, from preinfusion baseline. Within 30 min after administration of mevinolinic acid, HMG-CoA reductase activity was inhibited by at least 87%. At 0.5, 1.5, 3, 6, and 27 h after mevinolinic acid injection, cholesterol 7 alpha-hydroxylase activity was decreased by 6%, 25%, 54%, 41%, and 17%, respectively. By 27 h, the activities of both enzymes had returned to baseline levels. The reduction of bile acid synthesis correlated closely with the observed changes in the activities of cholesterol 7 alpha-hydroxylase. In vitro addition of mevinolinic acid (up to 20 microM) to rat liver microsomes failed to inhibit cholesterol 7 alpha-hydroxylase activity, suggesting no direct effect of mevinolinic acid on enzyme activity. When a bolus dose of mevinolinic acid was coupled with a continuous infusion of mevalonate, the product of the reaction catalyzed by HMG-CoA reductase, the mevinolinic acid-induced decrease in cholesterol 7 alpha- hydroxylase activity and bile acid synthesis was prevented. The results of this study provide evidence that, under the experimental conditions described, there is a linkage between the rates of cholesterol synthesis and the activities of cholesterol 7 alpha-hydroxylase. The data also emphasize the importance of the newly synthesized cholesterol in the regulation of cholesterol 7 alpha-hydroxylase activity.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				X. Li, W. M. Pandak, S. K. Erickson, Y. Ma, L. Yin, P. Hylemon, and S. Ren Biosynthesis of the regulatory oxysterol, 5-cholesten-3{beta},25-diol 3-sulfate, in hepatocytes J. Lipid Res., December 1, 2007; 48(12): 2587 - 2596. [Abstract] [Full Text] [PDF]

				W. M. Pandak, S. Ren, D. Marques, E. Hall, K. Redford, D. Mallonee, P. Bohdan, D. Heuman, G. Gil, and P. Hylemon Transport of Cholesterol into Mitochondria Is Rate-limiting for Bile Acid Synthesis via the Alternative Pathway in Primary Rat Hepatocytes J. Biol. Chem., December 6, 2002; 277(50): 48158 - 48164. [Abstract] [Full Text] [PDF]

				M.-A. Levrat-Verny, S. Behr, V. Mustad, C. Rémésy, and C. Demigné Low Levels of Viscous Hydrocolloids Lower Plasma Cholesterol in Rats Primarily by Impairing Cholesterol Absorption J. Nutr., January 1, 2000; 130(2): 243 - 248. [Abstract] [Full Text]

				C. Moundras, S. R. Behr, C. Rémésy, and C. Demigné Fecal Losses of Sterols and Bile Acids Induced by Feeding Rats Guar Gum Are Due to Greater Pool Size and Liver Bile Acid Secretion J. Nutr., June 1, 1997; 127(6): 1068 - 1076. [Abstract] [Full Text]