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Papers In Press, published online ahead of print March 1, 2009
J. Lipid Res., doi:10.1194/jlr.M800284-JLR200

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Journal of Lipid Research, Vol. 50, 376-385, March 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

VLDL best predicts aortic root atherosclerosis in LDL receptor deficient mice^*,

Paul A. VanderLaan^*, Catherine A. Reardon^*, Ronald A. Thisted and Godfrey S. Getz^1,*,

^* Departments of Pathology and Health Studies, University of Chicago, Chicago, IL 60637
Biostatistics, Epidemiology, and Health Services Research, University of Chicago, Chicago, IL 60637

^* This work was supported by the Cardiovascular Pathophysiology and Biochemistry Training grant HL007237 and the Medical Scientist Training Program grant GM007281 for P.A.V; NIH Clinical and Translational Science Award UL1 RR024999 for R.A.T; and NIH R01 grants HL056827, HL068661, and HL085516 for G.S.G.

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of a figure and a table.

Published, JLR Papers in Press, October 28, 2008.

¹ To whom correspondence should be addressed. e-mail: getz{at}bsd.uchicago.edu

Hyperlipidemia is a major risk factor for developing atherosclerosis in humans, and epidemiological studies have correlated specific lipoprotein levels with cardiovascular disease risk. Murine models of atherosclerosis rely on the induction of hyperlipidemia for vascular lesions to form, but the pathogenic contributions attributed to different lipoprotein populations are not well defined. To address this issue, we analyzed over 300 LDL receptor (LDLR) deficient mice that have been fed a high-fat diet and for which a full lipoprotein profile and aortic root atherosclerosis values were assessed. Overall, aortic root atherosclerosis is best predicted by plasma VLDL cholesterol levels with less predictive value derived from either LDL or HDL cholesterol. Triglyceride levels are more atherogenic in female mice, especially immune competent females, and depletion of the adaptive immune system leads to a global reduction in plasma lipid levels and aortic root lesion size yet does not appear to alter the atherogenic potential of individual lipoprotein subspecies. In contrast, HDL-cholesterol is a better predictor of aortic root atherosclerosis in apoE-deficient mice. In summary, this large scale analysis of high-fat diet fed LDLR deficient mice highlight the relationship between different plasma lipid components, especially VLDL-cholesterol, and aortic root atherosclerosis.

Supplementary key words hyperlipidemia • cholesterol • HDL

Abbreviations: FPLC, fast-protein liquid chromatography; LDLR, LDL receptor; RAG, recombination activating gene

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