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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 Westerterp^1,*,, Willeke de Haan^*,, Jimmy F. P. Berbée^*,, Louis M. Havekes^*,, and Patrick C. N. Rensen^*,

^* Netherlands Organization for Applied Scientific Research-Quality of Life, Department of Biomedical Research, Gaubius Laboratory, 2301 CE Leiden, The Netherlands
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; C_t, threshold cycle number; LDLr, low density lipoprotein receptor; TC, total cholesterol; TG, triglyceride; TO, triolein; WAT, white adipose tissue

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