Regulation of fatty acid biosynthesis by intermediates of the cholesterol biosynthetic pathway.
The biosynthesis of cholesterol and fatty acid (FA) proceeds by independent pathways. Information is lacking on potential interaction that could provide feedback regulation between these pathways. In an attempt to search for a new approach to produce a dual effect on regulation of these two processes, we have identified mevalonate-5-diphosphate (MevPP) decarboxylase, an enzyme of the cholesterol biosynthesis pathway, the inhibition of which leads not only to the suppression of cholesterol but also FA biosynthesis. Mechanistic studies with Hep G2 cells using specific inhibitors for MevPP decarboxylase and related enzymes reveal that the inhibitory effect on FA biosynthesis is mainly due to the accumulation of MevPP, resulting from MevPP decarboxylase inhibition. The present study proposes a new mechanism through which interpathway regulation could take place between the cholesterol and FA cascades.
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Research Department, CIBA Corporation, Summit, New Jersey 07901, USA.
D000924:Anticholesteremic Agents / Q000494:pharmacology; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors*; D006528:Carcinoma, Hepatocellular; D002784:Cholesterol / Q000096:biosynthesis*; D005227:Fatty Acids / Q000096:biosynthesis*; D006706:Homeostasis; D006801:Humans; D007700:Kinetics; D008113:Liver Neoplasms; D008148:Lovastatin / Q000494:pharmacology; D008798:Mevalonic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000924:Anticholesteremic Agents; D005227:Fatty Acids; C045174:6-fluoromevalonolactone; D002784:Cholesterol; D008148:Lovastatin; D002262:Carboxy-Lyases; C022503:pyrophosphomevalonate decarboxylase; D008798:Mevalonic Acid