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Papers In Press, published online ahead of print October 1, 2006
J. Lipid Res., doi:10.1194/jlr.M600146-JLR200

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Journal of Lipid Research, Vol. 47, 2215-2222, October 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Addition of dietary fat to cholesterol in the diets of LDL receptor knockout mice: effects on plasma insulin, lipoproteins, and atherosclerosis

Lan Wu^*, Reeba Vikramadithyan, Shuiqing Yu^*, Clara Pau^*, Yunying Hu, Ira J. Goldberg^*, and Hayes M. Dansky^1,*

^* Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, NY
Division of Preventative Medicine, Department of Medicine, Columbia University Medical Center, New York, NY

The online version of this article (available at http://www.jlr.org) contains four additional figures.

Published, JLR Papers in Press, July 13, 2006.

¹ To whom correspondence should be addressed. e-mail: hayes_dansky{at}merck.com

The factors underlying cardiovascular risk in patients with diabetes have not been clearly elucidated. Efforts to study this in mice have been hindered because the usual atherogenic diets that contain fat and cholesterol also lead to obesity and insulin resistance. We compared plasma glucose, insulin, and atherosclerotic lesion formation in LDL receptor knockout (Ldlr^–/–) mice fed diets with varying fat and cholesterol content that induced similar lipoprotein profiles. Ldlr^–/– mice fed a high-fat diet developed obesity, mild hyperglycemia, hyperinsulinemia, and hypertriglyceridemia. Quantitative and qualitative assessments of atherosclerosis were unchanged in diabetic Ldlr^–/– mice fed a high-fat diet compared with lean nondiabetic control mice after 20 weeks of diet. Although one group of mice fed diets for 40 weeks had larger lesions at the aortic root, this was associated with a more atherogenic lipoprotein profile. The presence of a human aldose reductase transgene had no effect on atherosclerosis in fat-fed Ldlr^–/– mice with mild diabetes. Our data suggest that when lipoprotein profiles are similar, addition of fat to a cholesterol-rich diet does not increase atherosclerotic lesion formation in Ldlr^–/– mice.

Supplementary key words diabetes • insulin resistance • aldose reductase

Abbreviations: ApoE, apolipoprotein E; AR, aldose reductase; FPLC, fast-protein liquid chromatography; HF1, high-fat diet 1; LF1, low-fat diet 1

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