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Endogenous apoC-I increases hyperlipidemia in apoE-knockout mice by stimulating VLDL production and inhibiting LPL

Author: Westerterp, M. · Haan, W. de · Berbée, J.F.P. · Havekes, L.M. · Rensen, P.C.N.
Institution: TNO Kwaliteit van Leven
Source:Journal of Lipid Research, 6, 47, 1203-1211
Identifier: 239295
doi: doi:10.1194/jlr.M500434-JLR200
Keywords: Biology · Lipases transgenic mouse models · Very low density lipoprotein · apolipoprotein B · cholesterol · fatty acid · heparin · lipid · olive oil · triacylglycerol · very low density lipoprotein · animal experiment · animal tissue · cholesterol blood level · concentration response · controlled study · enzyme inhibition · gene dosage · gonad · hyperlipidemia · intestine absorption · knockout mouse · lipid absorption · lipid blood level · lipid metabolism · lipolysis · mouse · nonhuman · postprandial state · protein expression · triacylglycerol blood level · white adipose tissue · Animals · Apolipoprotein C-I · Apolipoproteins C · Apolipoproteins E · Cholesterol · Hyperlipidemias · Intestines · Lipase · Lipoprotein Lipase · Lipoproteins, VLDL · Liver · Mice · Mice, Knockout · Postprandial Period


Previous studies have shown that overexpression of human apolipoprotein C-I (apoC-I) results in moderate hypercholesterolemia and severe hypertriglyceridemia in mice in the presence and absence of apoE. We assessed whether physiological endogenous apoC-I levels are sufficient to modulate plasma lipid levels independently of effects of apoE on lipid metabolism by comparing apolipoprotein E gene-deficient/apolipoprotein C-I gene-deficient (apoe -/-apoc1-/-), apoe-/-apoc +/-, and apoe-/-apoc1+/+ mice. The presence of the apoC-I gene-dose-dependently increased plasma cholesterol (+45%; P < 0.001) and triglycerides (TGs) (+137%; P < 0.001), both specific for VLDL. Whereas apoC-I did not affect intestinal [3H]TG absorption, it increased the production rate of hepatic VLDL-TG (+35%; P < 0.05) and VLDL-[ 35S]apoB (+39%; P < 0.01). In addition, apoC-I increased the postprandial TG response to an intragastric olive oil load (+120%; P < 0.05) and decreased the uptake of [3H]TG-derived FFAs from intravenously administered VLDL-like emulsion particles by gonadal and perirenal white adipose tissue (WAT) (-34% and -25%, respectively; P < 0.05). As LPL is the main enzyme involved in the clearance of TG-derived FFAs by WAT, and total postheparin plasma LPL levels were unaffected, these data demonstrate that endogenous apoC-I suffices to attenuate the lipolytic activity of LPL. Thus, we conclude that endogenous plasma apoC-I increases VLDL-total cholesterol and VLDL-TG dose-dependently in apoe-/- mice, resulting from increased VLDL particle production and LPL inhibition. Copyright © 2006 by the American Society for Biochemistry and Molecular Biology, Inc. Chemicals / CAS: cholesterol, 57-88-5; heparin, 37187-54-5, 8057-48-5, 8065-01-8, 9005-48-5; lipid, 66455-18-3; lipoprotein lipase, 83137-80-8, 9004-02-8; olive oil, 8001-25-0; Apolipoprotein C-I; Apolipoproteins C; Apolipoproteins E; Cholesterol, 57-88-5; Lipase, EC; Lipoprotein Lipase, EC; Lipoproteins, VLDL