Total hydroxymethylglutaryl CoA reductase activity in the small intestine and liver of insulin-deficient rats.

We examined the effect of streptozotocin-induced diabetes on the rate-limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl CoA reductase (EC 1.1.1.34), in liver and small intestine of rats. During the acute phase of insulin deficiency (first day), food intake, plasma cholesterol, and reductase specific activity in liver all decreased. By 3 days, food intake, plasma cholesterol, and reductase activity in small intestine were all increasing. After 1 week, total reductase activity in small intestine was 2.5 times normal, whereas activity in liver remained low. Thus diabetes shifted the major site of cholesterol synthesis from the liver to the small intestine. These data support the proposal that hyperphagia by diabetic rats leads to increased input of both dietary and newly synthesized cholesterol by the small intestine into thoracic lymph and thereby contributes significantly to their hypercholesterolemia. The possibility that diabetes affected the F--inhibitable activation of reductase in vitro was also tested. There was no evidence of an effect in small intestine, but activation of reductase in vitro was decreased by 1/3 in liver. These data suggest that, in liver, either the activity of the activator was decreased or the fraction of reductase in the active state was increased after more than 12 hr of insulin deficiency.