Diabetes increases hepatic hydroxymethyl glutaryl coenzyme A reductase protein and mRNA levels in the small intestine.

Previous studies have shown that both cholesterol synthesis and the activity of hepatic hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme in cholesterol synthesis, are increased in the small intestine of a wide variety of different animal models of diabetes. In the present study, we demonstrate that the mass of HMG CoA reductase protein is increased in the small intestine of both streptozocin-induced diabetic rats (2.5-fold) and streptozocin/alloxan-induced diabetic dogs (2.4-fold). These increases in HMG CoA reductase protein mass are of a magnitude similar to the previously observed increases in either HMG CoA reductase activity and/or cholesterol synthesis in the small intestine of diabetic animals. Furthermore, mRNA levels for HMG CoA reductase in the small intestine of diabetic rats and diabetic dogs are increased 2.1- and 1.7-fold, respectively. These results suggest that the increase in HMG CoA reductase protein levels in the small intestine of diabetic animals is due to an increase in mRNA levels. In contrast, mRNA levels for HMG CoA reductase in the liver of diabetic rats are not increased. Additionally, mRNA levels for the low-density lipoprotein (LDL) receptor are also increased in the small intestine of diabetic animals (rats, 43%; dogs, 59%). The increase in small-intestinal cholesterol synthesis has the potential for adversely affecting lipoprotein metabolism and increasing the risk of atherosclerosis in diabetes.