INSULIN AND GLUCAGON MODULATE HEPATIC 3-HYDROXY-3-METHYLGLUTARYL-COENZYME-A REDUCTASE-ACTIVITY BY AFFECTING IMMUNOREACTIVE PROTEIN-LEVELS

The question of whether the effects of insulin and glucagon on hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity ar e mediated largely by changes in the phosphorylation state of the enzy me or by changes in the quantity of enzyme protein was investigated by measuring enzyme protein and mRNA levels. If phosphorylation/dephosph orylation is responsible for the observed changes in HMG-CoA reductase activity, one would not expect to see changes in immunoreactive prote in or mRNA levels in response to induction of diabetes, administration of insulin, or administration of insulin and glucagon. It was found t hat hepatic HMG-CoA reductase mRNA levels were decreased to 12% of con trol in diabetic rats. Immunoreactive protein was reduced to essential ly undetectable levels. Administration of insulin restored both mRNA a nd immunoreactive protein levels. Glucagon blocked these effects. Enzy me activity changes were fully accounted for by changes in HMG-CoA red uctase mRNA and immunoreactive protein. Fasting caused parallel falls in HMG-CoA reductase activity and immunoreactive protein levels with a lesser effect on mRNA levels. The insulin-mediated changes in HMG-CoA reductase gene expression correlated well with changes in blood gluco se levels, indicating a physiological effect. Taken together, these re sults indicate that insulin and glucagon regulate HMG-CoA reductase ge ne expression largely at the level of enzyme protein through changes i n mRNA concentrations.