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J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M400301-JLR200 on December 1, 2004

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Journal of Lipid Research, Vol. 46, 297-306, February 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Severe hypertriglyceridemia in human APOC1 transgenic mice is caused by apoC-I-induced inhibition of LPL

Jimmy F. P. Berbée1,*,{dagger}, Caroline C. van der Hoogt*,{dagger}, Deepa Sundararaman*,{dagger}, Louis M. Havekes*,{dagger},§ and Patrick C. N. Rensen*,{dagger}

* Netherlands Organization for Applied Scientific Research-Prevention and Health, Gaubius Laboratory, 2301 CE Leiden, The Netherlands
{dagger} Departments of General Internal Medicine, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
§ Cardiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

1 To whom correspondence should be addressed. e-mail: jfp.berbee{at}pg.tno.nl

Studies in humans and mice have shown that increased expression of apolipoprotein C-I (apoC-I) results in combined hyperlipidemia with a more pronounced effect on triglycerides (TGs) compared with total cholesterol (TC). The aim of this study was to elucidate the main reason for this effect using human apoC-I-expressing (APOC1) mice. Moderate plasma human apoC-I levels (i.e., 4-fold higher than human levels) caused a 12-fold increase in TG, along with a 2-fold increase in TC, mainly confined to VLDL. Cross-breeding of APOC1 mice on an apoE-deficient background resulted in a marked 55-fold increase in TG, confirming that the apoC-I-induced hyperlipidemia cannot merely be attributed to blockade of apoE-recognizing hepatic lipoprotein receptors. The plasma half-life of [3H]TG-VLDL-mimicking particles was 2-fold increased in APOC1 mice, suggesting that apoC-I reduces the lipolytic conversion of VLDL. Although total postheparin plasma LPL activity was not lower in APOC1 mice compared with controls, apoC-I was able to dose-dependently inhibit the LPL-mediated lipolysis of [3H]TG-VLDL-mimicking particles in vitro with a 60% efficiency compared with the main endogenous LPL inhibitor apoC-III. Finally, purified apoC-I impaired the clearance of [3H]TG-VLDL-mimicking particles independent of apoE-mediated hepatic uptake in lactoferrin-treated mice.

Therefore, we conclude that apoC-I is a potent inhibitor of LPL-mediated TG-lipolysis.

Abbreviations: apoC-I, apolipoprotein C-I; APOC1, human apolipoprotein C-I-encoding gene; apoe–/–, apolipoprotein E-deficient mice; CETP, cholesteryl ester transfer protein; CO, cholesteryl oleate; FC, free cholesterol; FPLC, fast-performance liquid chromatography; LDLr, low density lipoprotein receptor; LRP, low density lipoprotein receptor-related protein; TC, total cholesterol; TG, triglyceride; TO, triolein; VLDLr, very low density lipoprotein receptor

Supplementary key words fatty acids • lipid metabolism • triglycerides • apolipoprotein C-I • very low density lipoprotein • lipoprotein lipase


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