Endogenous apoC-I increases hyperlipidemia in apoE-knockout mice by stimulating VLDL production and inhibiting LPL
article
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 3.1.1.3; Lipoprotein Lipase, EC 3.1.1.34; Lipoproteins, VLDL
Topics
Lipases transgenic mouse modelsVery low density lipoproteinapolipoprotein Bcholesterolfatty acidheparinlipidolive oiltriacylglycerolvery low density lipoproteinanimal experimentanimal tissuecholesterol blood levelconcentration responsecontrolled studyenzyme inhibitiongene dosagegonadhyperlipidemiaintestine absorptionknockout mouselipid absorptionlipid blood levellipid metabolismlipolysismousenonhumanpostprandial stateprotein expressiontriacylglycerol blood levelwhite adipose tissueAnimalsApolipoprotein C-IApolipoproteins CApolipoproteins ECholesterolHyperlipidemiasIntestinesLipaseLipoprotein LipaseLipoproteins, VLDLLiverMiceMice, KnockoutPostprandial Period
TNO Identifier
239295
ISSN
00222275
Source
Journal of Lipid Research, 47(6), pp. 1203-1211.
Pages
1203-1211