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Regulation of early cholesterol biosynthesis in rat liver: Effects of sterols, bile acids, lovastatin, and BM 15.766 on 3‐hydroxy‐3‐methylglutaryl coenzyme A synthase and acetoacetyl coenzyme A thiolase activities
Author(s) -
Honda Akira,
Salen Gerald,
Nguyen Lien B.,
Xu Guorong,
Tint G. Stephen,
Batta Ashok K.,
Shefer Sarah
Publication year - 1998
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510270124
Subject(s) - thiolase , lovastatin , reductase , hmg coa reductase , coenzyme a , biochemistry , mevalonic acid , hydroxymethylglutaryl coa reductase , cholestyramine , cyp8b1 , cholic acid , bile acid , cholesterol , 7 dehydrocholesterol reductase , biology , chemistry , enzyme , medicine , dehydrogenase
Cytosolic 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) synthase catalyzes the formation of HMG‐CoA, the substrate for the rate‐controlling enzyme in the cholesterol biosynthetic pathway. To explore the regulation in liver, we developed a new, accurate, and reliable reversed‐phase ion‐pair chromatographic assay that uses nonradioactive substrates and n ‐propionyl coenzyme A as an internal recovery standard. The hepatic activities were measured in rats treated with cholesterol, sitosterol, cholic acid, deoxycholic acid, ursodeoxycholic acid, cholestyramine, bile fistula, lovastatin, and BM 15.766, an inhibitor of 7‐dehydrocholesterol Δ 7 ‐reductase, and were compared with microsomal HMG‐CoA reductase and cytosolic acetoacetyl coenzyme A (AcAc‐CoA) thiolase activities. HMG‐CoA synthase activity was effectively suppressed in synchrony with HMG‐CoA reductase activity by treatments with cholesterol (−41%, P < .05), cholic acid (−72%, P < .005), and deoxycholic acid (−62%, P < .05). However, ursodeoxycholic acid increased activity 84% ( P < .05) and intravenous sitosterol did not change activity. AcAc‐CoA thiolase activities also paralleled HMG‐CoA reductase and HMG‐CoA synthase activities, but differences were not statistically significant. In contrast to inhibition, up‐regulation of hepatic HMG‐CoA synthase activities by cholestyramine, bile fistula, and lovastatin was much less than HMG‐CoA reductase activities. In addition, BM 15.766 did not stimulate synthase activity, whereas lovastatin increased activity 2.4‐fold. Thus, hepatic HMG‐CoA synthase activity was regulated coordinately with HMG‐CoA reductase, and responded more forcefully to regulatory stimuli than acetoacetyl‐CoA thiolase activity but usually less than HMG‐CoA reductase.