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ApoC-III deficiency prevents hyperlipidemia induced by apoE overexpression

Author: Gerritsen, G. · Rensen, P.C.N. · Kypreos, K.E. · Zannis, V.I. · Havekes, L.M. · Dijk, K.W. van
Type:article
Date:2005
Institution: TNO Kwaliteit van Leven
Source:Journal of Lipid Research, 7, 46, 1466-1473
Identifier: 238952
doi: doi:10.1194/jlr.M400479-JLR200
Keywords: Biology · Biomedical Research · Adenovirus-mediated gene transfer · Lipoprotein lipase-mediated triglyceride hydrolysis · Mice · Very low density lipoprotein · Cholesterol · Fatty acid · Intermediate density lipoprotein · Lipoprotein · Triacylglycerol · Lipid · Lipoprotein lipase · Animal experiment · Animal tissue · Cholesterol blood level · Controlled study · Dose response · Emulsion · Female · Gene dosage · Gene overexpression · Hydrolysis · Hyperlipidemia · In vitro study · In vivo study · Injection · Lipoprotein deficiency · Mouse · Nonhuman · Protein blood level · White adipose tissue · Animal · Biosynthesis · Blood · Genetic transfection · Genetics · Metabolism · Mouse mutant · Animals · Apolipoprotein C-III · Apolipoprotein E4 · Apolipoproteins C · Apolipoproteins E · Humans · Hyperlipidemias · Lipids · Lipoprotein Lipase · Lipoproteins · Lipoproteins, VLDL · Mice · Mice, Knockout · Transfection · Triglycerides

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. Chemicals / CAS: cholesterol, 57-88-5; lipid, 66455-18-3; lipoprotein lipase, 83137-80-8, 9004-02-8; Apolipoprotein C-III; Apolipoprotein E4; Apolipoproteins C; Apolipoproteins E; Lipids; Lipoprotein Lipase, EC 3.1.1.34; Lipoproteins; Lipoproteins, VLDL; Triglycerides