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J. Biol. Chem., Vol. 279, Issue 27, 27941-27947, July 2, 2004
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ApoAV Reduces Plasma Triglycerides by Inhibiting Very Low Density Lipoprotein-Triglyceride (VLDL-TG) Production and Stimulating Lipoprotein Lipase-mediated VLDL-TG Hydrolysis*
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¶¶
From the
AMC Liver Center, Meibergdreef 69-71, 1105 BK Amsterdam, The Netherlands, ||TNO-Prevention and Health, Gaubius Laboratory, Zernikedreef 9, 2333 CK Leiden, The Netherlands, and the Departments of **General Internal Medicine, Endocrinology, Human Genetics, and ¶¶Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
ApoAV has been discovered recently as a novel modifier of triglyceride (TG) metabolism, but the pathways involved are currently unknown. To gain insight into the function of apoAV, adenovirus-mediated gene transfer of murine apoa5 to C57Bl/6 mice was employed. The injection of low doses of Ad-apoa5 (1–5 x 108 plaqueforming units/mouse) dose-dependently reduced plasma very low density lipoprotein (VLDL)-TG levels. First, we evaluated whether a reduced hepatic VLDL production contributed to the TG-lowering effect. Ad-apoa5 treatment dose-dependently diminished (29–37%) the VLDL-TG production rate without affecting VLDL particle production, suggesting that apoAV impairs the lipidation of apoB. Second, Ad-apoa5 treatment dose-dependently reduced (68–88%) the postprandial hypertriglyceridemia following an intragastric fat load, suggesting that apoAV also stimulates the lipoprotein lipase (LPL)-dependent clearance of TG-rich lipoproteins. Indeed, recombinant apoAV was found to dose-dependently stimulate LPL activity up to 2.3-fold in vitro. Accordingly, intravenously injected VLDL-like TG-rich emulsions were cleared at an accelerated rate concomitant with the increased uptake of emulsion TG-derived fatty acids by skeletal muscle and white adipose tissue in Ad-apoa5-treated mice. From these data, we conclude that apoAV is a potent stimulator of LPL activity. Thus, apoAV lowers plasma TG by both reducing the hepatic VLDL-TG production rate and by enhancing the lipolytic conversion of TG-rich lipoproteins.
Received for publication, March 23, 2004 , and in revised form, April 15, 2004.
* This work was conducted in the framework of the "Leiden Center for Cardiovascular Research LUMC-TNO" and supported in part by a Meelmeyer grant from the Amsterdam Academic Medical Center (to F. G. S.), a Gisela Thier Fellowship from Leiden University Medical Center (to P. C. N. R.), and the NWO VIDI Grant 917-36-351) (to P. C. N. R.) and NWO Program Grant 903-39-291 (to L. M. H.) from the Netherlands Organization for Scientific Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Both authors equally contributed to this work.
¶ To whom correspondence should be addressed. Tel.: 31-20-566-8162; Fax: 31-20-566-9190; E-mail: f.g.schaap{at}amc.uva.nl.
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