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 are mediated largely by changes in the phosphorylation state of the enzyme or by changes in the quantity of enzyme protein was investigated by measuring enzyme protein and mRNA levels. If phosphorylation/dephosphorylation is responsible for the observed changes in HMG-CoA reductase activity, one would not expect to see changes in immunoreactive protein or mRNA levels in response to induction of diabetes, administration of insulin, or administration of insulin and glucagon. It was found that hepatic HMG-CoA reductase mRNA levels were decreased to 12% of control in diabetic rats. Immunoreactive protein was reduced to essentially undetectable levels. Administration of insulin restored both mRNA and immunoreactive protein levels. Glucagon blocked these effects. Enzyme activity changes were fully accounted for by changes in HMG-CoA reductase 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 glucose levels, indicating a physiological effect. Taken together, these results indicate that insulin and glucagon regulate HMG-CoA reductase gene expression largely at the level of enzyme protein through changes in mRNA concentrations.