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Journal of Lipid Research, Vol. 46, 297-306, February 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology
,
* Netherlands Organization for Applied Scientific Research-Prevention and Health, Gaubius Laboratory, 2301 CE Leiden, The Netherlands
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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