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Originally published In Press as doi:10.1194/jlr.M500434-JLR200 on March 14, 2006

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Journal of Lipid Research, Vol. 47, 1203-1211, June 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Endogenous apoC-I increases hyperlipidemia in apoE-knockout mice by stimulating VLDL production and inhibiting LPL

Marit Westerterp1,*,{dagger}, Willeke de Haan*,{dagger}, Jimmy F. P. Berbée*,{dagger}, Louis M. Havekes*,{dagger},§ and Patrick C. N. Rensen*,{dagger}

* Netherlands Organization for Applied Scientific Research-Quality of Life, Department of Biomedical Research, Gaubius Laboratory, 2301 CE Leiden, The Netherlands
{dagger} Departments of General Internal Medicine, Endocrinology, and Metabolism, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
§ Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

Published, JLR Papers in Press, March 14, 2006.

1 To whom correspondence should be addressed. e-mail: m.westerterp{at}lumc.nl

Previous studies have shown that overexpression of human apolipoprotein C-I (apoC-I) results in moderate hypercholesterolemia and severe hypertriglyceridemia in mice in the presence and absence of apoE. We assessed whether physiological endogenous apoC-I levels are sufficient to modulate plasma lipid levels independently of effects of apoE on lipid metabolism by comparing apolipoprotein E gene-deficient/apolipoprotein C-I gene-deficient (apoe–/–apoc1–/–), apoe–/–apoc1+/–, and apoe–/–apoc1+/+ mice. The presence of the apoC-I gene-dose-dependently increased plasma cholesterol (+45%; P < 0.001) and triglycerides (TGs) (+137%; P < 0.001), both specific for VLDL. Whereas apoC-I did not affect intestinal [3H]TG absorption, it increased the production rate of hepatic VLDL-TG (+35%; P < 0.05) and VLDL-[35S]apoB (+39%; P < 0.01). In addition, apoC-I increased the postprandial TG response to an intragastric olive oil load (+120%; P < 0.05) and decreased the uptake of [3H]TG-derived FFAs from intravenously administered VLDL-like emulsion particles by gonadal and perirenal white adipose tissue (WAT) (–34% and –25%, respectively; P < 0.05). As LPL is the main enzyme involved in the clearance of TG-derived FFAs by WAT, and total postheparin plasma LPL levels were unaffected, these data demonstrate that endogenous apoC-I suffices to attenuate the lipolytic activity of LPL. Thus, we conclude that endogenous plasma apoC-I increases VLDL-total cholesterol and VLDL-TG dose-dependently in apoe–/– mice, resulting from increased VLDL particle production and LPL inhibition.

Supplementary key words apolipoprotein C-I • apolipoprotein E • lipases • transgenic mouse models • lipoprotein lipase • very low density lipoprotein

Abbreviations: apoC-I, apolipoprotein C-I; apoe–/–, apolipoprotein E gene-deficient; Ct, threshold cycle number; LDLr, low density lipoprotein receptor; TC, total cholesterol; TG, triglyceride; TO, triolein; WAT, white adipose tissue


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