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A more recent version of this article appeared on February 1, 2005

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J. Lipid Res., doi:10.1194/jlr.M400301-JLR200
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Submitted on August 9, 2004
Revised on October 27, 2004
Accepted on November 18, 2004

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

Jimmy F.P. Berbée, Caroline C. van der Hoogt, Deepa Sundararaman, Louis M. Havekes, and Patrick C.N. Rensen

Biomedical research, TNO-Prevention and Health, and Leiden University Medical Center, Leiden 2301 CE

Corresponding Author: jfp.berbee{at}pg.tno.nl

Studies in humans and mice have shown that increased expression of apoCI results in combined hyperlipidemia with a more pronounced effect on triglycerides (TG) as compared to total cholesterol (TC). The aim of this study was to elucidate the main reason for this effect using human apoCI-expressing (APOC1) mice. Moderate plasma human apoCI 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 apoCI-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 apoCI reduces the lipolytic conversion of VLDL. While total post-heparin plasma LPL activity was not lower in APOC1 mice as compared to controls, apoCI was able to dose-dependently inhibit the LPL-mediated lipolysis of [3H]TG-VLDL-mimicking particles in vitro, with a 60% efficiency as compared to the main endogenous LPL inhibitor apoCIII. Finally, purified apoCI impaired the clearance of [3H]TG-VLDL-mimicking particles independent of apoE-mediated hepatic uptake, in lactoferrin-treated mice. Therefore, we conclude that apoCI is a potent inhibitor of LPL-mediated TG-lipolysis.


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