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Journal of Lipid Research, Vol. 43, 2136-2145, December 2002
Copyright © 2002 by Lipid Research, Inc.

Overexpression of apoC-I in apoE-null mice

Karin Conde-Knape^*, André Bensadoun, Joan H. Sobel^*, Jeffrey S. Cohn and Neil S. Shachter^1,*

^* Department of Medicine, Columbia University, 630 W. 168th Street, New York, NY
Divisions of Nutritional and Biological Sciences, Cornell University, Ithaca, NY
Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada

¹ To whom correspondence should be addressed. e-mail: nss5{at}columbia.edu

Apolipoprotein C-I (apoC-I) has been proposed to act primarily via interference with apoE-mediated lipoprotein uptake. To define actions of apoC-I that are independent of apoE, we crossed a moderately overexpressing human apoC-I transgenic, which possesses a minimal phenotype in the WT background, with the apoE-null mouse. Surprisingly, apoE-null/C-I mice showed much more severe hyperlipidemia than apoE-null littermates in both the fasting and non-fasting states, with an almost doubling of cholesterol, primarily in IDL+LDL, and a marked increase in triglycerides; 3-fold in females to 260 ± 80 mg/dl and 14-fold in males to 1409 ± 594 mg/dl. HDL lipids were not significantly altered but HDL were apoC-I-enriched and apoA-II-depleted. Production rates of VLDL triglyceride were unchanged as was the clearance of post-lipolysis remnant particles. Plasma post-heparin hepatic lipase and lipoprotein lipase levels were undiminished as was the in vitro hydrolysis of apoC-I transgenic VLDL. However, HDL from apoC-I transgenic mice had a marked inhibitory effect on hepatic lipase activity, as did purified apoC-I. LPL activity was minimally affected. Atherosclerosis assay revealed significantly increased atherosclerosis in apoE-null/C-I mice assessed via the en face assay.

Inhibition of hepatic lipase may be an important mechanism of the decrease in lipoprotein clearance mediated by apoC-I.

Abbreviations: apo, apolipoprotein; apoE0, apoE gene knockout; Chol, cholesterol; CI, human apoC-I transgenic; E0CI, homozygous for the apoE0 allele and hemizygous for the human apoC-I transgene; HDL-C, HDL cholesterol; HL, hepatic lipase; LDLR, LDL receptor; LRP, LDL receptor-related protein

Supplementary key words lipoproteins • VLDL • mutant strains

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