doi: 10.1161/hq0102.102588
© 2002 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Transgenic Expression of Cholesterol-7-
-Hydroxylase Prevents Atherosclerosis in C57BL/6J Mice
From the Mammalian Cell and Molecular Biology Laboratory (J.H.M., X.T.D.-P., E.Z.D., R.A.D.), San Diego State University, San Diego, Calif; the Gladstone Institute of Cardiovascular Disease (J.M.T.), University of California, San Francisco; and the Department of Microbiology and Molecular Genetics (L.W.C., A.J.L.), UCLA, Los Angeles, Calif.
Correspondence to Dr Roger A. Davis, Department of Biology, LS307, 5300 Campanile Dr, San Diego State University, San Diego, CA 92182-4614. E-mail rdavis{at}SUNSTROKE.sdsu.edu
C57BL/6J mice are susceptible to atherosclerosis when fed a diet consisting of fat, cholesterol, and taurocholate. The susceptibility to diet-induced atherosclerosis is linked to a reduction in plasma high density lipoprotein (HDL). Diet-induced reduction of plasma HDL shows a physiological and a genetic correlation with repression of cholesterol-7-
-hydroxylase, the liver-specific enzyme that regulates the conversion of cholesterol into bile acids. To examine the hypothesis that the repression of cholesterol-7--hydroxylase is responsible for initiating the metabolic alterations leading to the formation of atherosclerosis and gallstones, we determined whether constitutive transgenic expression of cholesterol-7--hydroxylase in C57BL/6J mice would confer resistance to these 2 common human diseases. When fed the atherogenic diet, nontransgenic littermates, but not cholesterol-7--hydroxylase transgenic mice, accumulated cholesterol and cholesterol esters in their livers and plasma. Although the atherogenic diet caused a marked decrease in plasma HDL cholesterol in nontransgenic mice, HDL levels in transgenic mice remained relatively unchanged. Moreover, the ability of cholesterol-7--hydroxylase transgenic mice to maintain cholesterol and lipoprotein homeostasis completely prevented the formation of atherosclerosis and gallstones. These data establish the integral role that cholesterol-7--hydroxylase has in maintaining hepatic cholesterol homeostasis and, thus, in the susceptibility to the formation of gallstones and atherosclerosis.
Key Words: atherosclerosis • bile acids • cholesterol-7--hydroxylase • gallstones • lipoproteins
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