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ORIGINAL RESEARCH ARTICLE

Increased Sensitivity to Dietary Cholesterol in Diabetic and Hypothyroid Rats Associated with Low Levels of Hepatic HMG-CoA Reductase Expression

Department of Biochemistry and Molecular Biology, College of Medicine, University of South Florida, Tampa, Florida 33612

To whom requests for reprints should be addressed at ¹ Department of Biochemistry and Molecular Biology, College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, FL 33612. E-mail: gness{at}hsc.usf.edu

We recently postulated that hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase functions as a cholesterol buffer to protect against the serum and tissue cholesterol raising action of dietary cholesterol. This postulate predicts that diminished basal expression of hepatic HMG-CoA reductase results in increased sensitivity to dietary cholesterol. Because diabetic and hypothyroid animals are known to have markedly reduced hepatic HMG-CoA reductase, these animals were selected as models to test our postulate. When rats were rendered diabetic with streptozotocin, their hepatic HMG-CoA reductase activity decreased from 314 to 22 pmol · min^–1 · mg^–1, and their serum cholesterol levels increased slightly. When the diabetic animals were challenged with a diet containing 1% cholesterol, their serum cholesterol levels doubled, and their hepatic reductase activity decreased further to 0.9 pmol · min^–1 · mg^–1. Hepatic low-density lipoprotein (LDL) receptor immunoreactive protein levels were unaffected in the diabetic rats whether fed cholesterol-supplemented diets or not. In rats rendered hypothyroid by thyroparathyroidectomy, serum cholesterol levels rose from 100 to 386 mg/dl in response to the 1% cholesterol challenge, whereas HMG-CoA reductase activity dropped from 33.8 to 3.4 pmol · min^–1 · mg^–1. Hepatic LDL receptor immunoreactive protein levels decreased only slightly in the hypothyroid rats fed cholesterol-supplemented diets. Taken together, these results show that rats deficient in either insulin or thyroid hormone are extremely sensitive to dietary cholesterol largely due to low basal expression of hepatic HMG-CoA reductase.

Key Words: HMG-CoA reductase • liver • insulin • thyroid hormone • serum cholesterol

This article has been cited by other articles:

				G. C. Ness, R. C. Holland, and D. Lopez Selective Compensatory Induction of Hepatic HMG-CoA Reductase in Response to Inhibition of Cholesterol Absorption. Experimental Biology and Medicine, May 1, 2006; 231(5): 559 - 565. [Abstract] [Full Text] [PDF]

				W. R. Lagor, E. D. de Groh, and G. C. Ness Diabetes Alters the Occupancy of the Hepatic 3-Hydroxy-3-methylglutaryl-CoA Reductase Promoter J. Biol. Chem., November 4, 2005; 280(44): 36601 - 36608. [Abstract] [Full Text] [PDF]