Rapid decrease in the expression of 3-hydroxy-3-methylglutaryl-CoA reductase protein owing to inhibition of its rate of synthesis after Ca super(2+) mobilization in rat hepatocytes: Inability of taurolithocholate to mimic the effect

The mechanisms through which Ca super(2+) mobilization in rat hepatocytes results in the loss of total activity of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase were investigated. The loss of total activity was shown to be paralleled by an equal loss of immunoreactive HMG-CoA reductase protein after exposure of hepatocytes to optimal concentrations of vasopressin plus glucagon for 40 min. This loss of enzyme protein was due to an inhibition of enzyme synthesis; the rate of degradation was unaffected. Other Ca super(2+)-mobilizing conditions (phenylephrine, glucagon, vasopressin added singly and A23187) also resulted in graded inhibition of synthesis of HMG-CoA reductase. These effects were accentuated by omission of Ca super(2+) from the cell incubation medium, suggesting that it is the depletion of an intracellular InsP sub(3)-sensitive pool of Ca super(2+) to which synthesis of HMG-CoA reductase is sensitive. In agreement with this we found that t-butylhydroxybenzoquinone, which inhibits the activity of the Ca super(2+)-ATPase of the endoplasmic-reticular membrane, mimicked the action of Ca super(2+)-mobilizing hormones.