Transgenic expression of cholesterol-7-alpha-hydroxylase prevents atherosclerosis in C57BL/6J mice.
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-alpha-hydroxylase, the liver-specific enzyme that regulates the conversion of cholesterol into bile acids. To examine the hypothesis that the repression of cholesterol-7-alpha-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-alpha-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-alpha-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-alpha-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-alpha-hydroxylase has in maintaining hepatic cholesterol homeostasis and, thus, in the susceptibility to the formation of gallstones and atherosclerosis.
Miyake
Jon H
JH
Mammalian Cell and Molecular Biology Laboratory, San Diego State University, San Diego, CA, USA.
Duong-Polk
Xuandao T
XT
Taylor
John M
JM
Du
Emma Z
EZ
Castellani
Lawrence W
LW
Lusis
Aldons J
AJ
Davis
Roger A
RA
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D002769:Cholelithiasis / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis* / Q000235:genetics; D008076:Cholesterol, HDL / Q000378:metabolism*; D004036:Diet, Atherogenic; D004198:Disease Susceptibility; D004794:Enzyme Repression; D005260:Female; D005704:Gallbladder / Q000378:metabolism; D006706:Homeostasis; D008074:Lipoproteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012727:Sex Characteristics
D008076:Cholesterol, HDL; D008074:Lipoproteins; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase