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

Abstract

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.

• Authors: W M Pandak, D M Heuman, P B Hylemon, Z R Vlahcevic
• Journal: Journal of lipid research (J Lipid Res) Vol. 31 Issue 1 Pg. 79-90 (Jan 1990) ISSN: 0022-2275 [Print] United States
• PMID: 2313206 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Bile Acids and Salts
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• mevalonolactone
• mevinolinic acid
• Cholesterol
• Lovastatin
• Hydroxymethylglutaryl CoA Reductases
• Cholesterol 7-alpha-Hydroxylase
• Mevalonic Acid

Topics

• Animals
• Bile Acids and Salts (biosynthesis)
• Cholesterol (biosynthesis)
• Cholesterol 7-alpha-Hydroxylase (metabolism)
• Hydroxymethylglutaryl CoA Reductases (metabolism)
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Lovastatin (analogs & derivatives, pharmacology)
• Male
• Mevalonic Acid (analogs & derivatives, pharmacology)
• Microsomes, Liver (drug effects, metabolism)
• Rats
• Rats, Inbred Strains