ApoC-III deficiency prevents hyperlipidemia induced by apoE overexpression

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Abstract

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 × 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. Copyright © 2005 by the American Society for Biochemistry and Molecular Biology, Inc.

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Gerritsen, G., Rensen, P. C. N., Kypreos, K. E., Zannis, V. I., Havekes, L. M., & Van Dijk, K. W. (2005). ApoC-III deficiency prevents hyperlipidemia induced by apoE overexpression. Journal of Lipid Research, 46(7), 1466–1473. https://doi.org/10.1194/jlr.M400479-JLR200

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