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Journal of Lipid Research, Vol. 46, 1466-1473, July 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

ApoC-III deficiency prevents hyperlipidemia induced by apoE overexpression

Gery Gerritsen^*, Patrick C. N. Rensen^,, Kyriakos E. Kypreos^*,**, Vassilis I. Zannis^**, Louis M. Havekes^,, and Ko Willems van Dijk^1,*,

^* Departments of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
Cardiology, Leiden University Medical Center, Leiden, The Netherlands
Netherlands Organization for Applied Scientific Research Quality of Life, Gaubius Laboratory, Leiden, The Netherlands
^** Boston University School of Medicine, Boston, MA

Published, JLR Papers in Press, May 1, 2005. DOI 10.1194/jlr.M400479-JLR200

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

Adenovirus-mediated overexpression of human apolipoprotein E (apoE) induces hyperlipidemia by stimulating the VLDL-triglyceride (TG) production rate and inhibiting the LPL-mediated VLDL-TG hydrolysis rate. Because apoC-III is a strong inhibitor of TG hydrolysis, we questioned whether Apoc3 deficiency might prevent the hyperlipidemia induced by apoE overexpression in vivo. Injection of 2 x 10⁹ plaque-forming units of AdAPOE4 caused severe combined hyperlipidemia in Apoe^–/– mice [TG from 0.7 ± 0.2 to 57.2 ± 6.7 mM; total cholesterol (TC) from 17.4 ± 3.7 to 29.0 ± 4.1 mM] that was confined to VLDL/intermediate density lipoprotein-sized lipoproteins. In contrast, Apoc3 deficiency resulted in a gene dose-dependent reduction of the apoE4-associated hyperlipidemia (TG from 57.2 ± 6.7 mM to 21.2 ± 18.5 and 1.5 ± 1.4 mM; TC from 29.0 ± 4.1 to 16.4 ± 9.8 and 2.3 ± 1.8 mM in Apoe^–/–, Apoe^–/–.Apoc3^+/–, and Apoe^–/–.Apoc3^–/– mice, respectively). In both Apoe^–/– mice and Apoe^–/–.Apoc3^–/– mice, injection of increasing doses of AdAPOE4 resulted in up to a 10-fold increased VLDL-TG production rate. However, Apoc3 deficiency resulted in a significant increase in the uptake of TG-derived fatty acids from VLDL-like emulsion particles by white adipose tissue, indicating enhanced LPL activity. In vitro experiments showed that apoC-III is a more specific inhibitor of LPL activity than is apoE.

Thus, Apoc3 deficiency can prevent apoE-induced hyperlipidemia associated with a 10-fold increased hepatic VLDL-TG production rate, most likely by alleviating the apoE-induced inhibition of VLDL-TG hydrolysis.

Abbreviations: apoE, apolipoprotein E; FPLC, fast-protein liquid chromatography; pfu, plaque-forming units; TC, total cholesterol; TG, triglyceride; TO, triolein; WAT, white adipose tissue

Supplementary key words lipoprotein lipase-mediated triglyceride hydrolysis • adenovirus-mediated gene transfer • mice • very low density lipoprotein • apolipoprotein E • apolipoprotein C-III

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