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.
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 delta7-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.
Honda
A
A
Department of Medicine and Liver Center, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, USA.
Salen
G
G
Nguyen
L B
LB
Xu
G
G
Tint
G S
GS
Batta
A K
AK
Shefer
S
S
D000101:Acetyl-CoA C-Acetyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000494:pharmacology; D002784:Cholesterol / Q000096:biosynthesis*; D002792:Cholestyramine Resin / Q000494:pharmacology; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013261:Sterols / Q000494:pharmacology
D000924:Anticholesteremic Agents; D001647:Bile Acids and Salts; D010879:Piperazines; D013261:Sterols; D002792:Cholestyramine Resin; C047457:BM 15766; D002784:Cholesterol; D008148:Lovastatin; D000101:Acetyl-CoA C-Acetyltransferase; D006904:Hydroxymethylglutaryl-CoA Synthase