ApoC-III deficiency prevents hyperlipidemia induced by apoE overexpression

• Published in: Journal of lipid research 2005-07, Vol.46 (7), p.1466-1473
• Main Authors: Gerritsen, Gery, Rensen, Patrick C. N, Kypreos, Kyriakos E, Zannis, Vassilis I, Havekes, Louis M, Willems van Dijk, Ko
• Format: Article
• Language: English
• Subjects: adenovirus-mediated gene transfer; Animals; Apolipoprotein C-III; apolipoprotein E; Apolipoprotein E4; Apolipoproteins C - deficiency; Apolipoproteins E - biosynthesis; Apolipoproteins E - genetics; Humans; Hyperlipidemias - genetics; Hyperlipidemias - prevention & control; Lipids - blood; Lipoprotein Lipase - metabolism; lipoprotein lipase-mediated triglyceride hydrolysis; Lipoproteins - blood; Lipoproteins, VLDL - blood; Mice; Mice, Knockout; Transfection; Triglycerides - blood; very low density lipoprotein
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M400479-JLR200

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⁻[superscript /]⁻ 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⁻[superscript /]⁻, Apoe⁻[superscript /]⁻.Apoc3⁺[superscript /]⁻, and Apoe⁻[superscript /]⁻.Apoc3⁻[superscript /]⁻ mice, respectively). In both Apoe⁻[superscript /]⁻ mice and Apoe⁻[superscript /]⁻.Apoc3⁻[superscript /]⁻ 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.