Evidence for post-transcriptional regulation by insulin of 3-hydroxy-3-methylglutaryl coenzyme A reductase and sterol synthesis in human mononuclear leucocytes.
Incubation of freshly isolated human mononuclear leucocytes in lipid-depleted serum for 4 h resulted in a two-fold increase in 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity. Insulin, when added to the incubation medium at concentrations of 10 and 100 nmol/l at zero time, caused additional increases in the enzyme activity of 30% and 37%, respectively. The hormone action was not immediate because no effect was observed when insulin was added at 4 h and activity examined thereafter. Under these conditions sterol synthesis from 14C-acetate and tritiated water was strictly proportional to the activity of HMG-CoA reductase. Cycloheximide (20 micrograms/ml), a translational inhibitor of protein synthesis, prevented the insulin-mediated increase in the enzyme activity and the incorporation of 14C-acetate into sterols. Cordycepin (50 micrograms/ml) inhibited messenger RNA synthesis by greater than 50%, but had no inhibitory effect on the induction of HMG-CoA reductase and sterol synthesis. Low density lipoprotein (80 micrograms protein/ml) and complete serum blocked the induction of the enzyme and sterol synthesis from 14C-acetate caused by lipid-depleted serum. The insulin-effect, however, remained unchanged. The results suggest that insulin may regulate the de novo synthesis of HMG-CoA reductase and accordingly sterol synthesis at a post-transcriptional level.
D000085:Acetates / Q000378:metabolism; D000241:Adenosine / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D003839:Deoxyadenosines / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis*; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis; D013261:Sterols / Q000096:biosynthesis*
D000085:Acetates; D003839:Deoxyadenosines; D007328:Insulin; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D013261:Sterols; D003513:Cycloheximide; D006903:Hydroxymethylglutaryl CoA Reductases; D000241:Adenosine