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J. Biol. Chem., Vol. 280, Issue 22, 21553-21560, June 3, 2005
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From the
Department of Internal Medicine I and ||IBM II, Molecular Cell Biology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany and ¶Genome Sciences Department, Lawrence Berkeley National Laboratory, Berkeley, California 94720
Apolipoprotein A5 (APOA5) is associated with differences in triglyceride levels and familial combined hyperlipidemia. In genetically engineered mice, apoAV plasma levels are inversely correlated with plasma triglycerides. To elucidate the mechanism by which apoAV influences plasma triglycerides, metabolic studies and in vitro assays resembling physiological conditions were performed. In human APOA5 transgenic mice (hAPOA5tr), catabolism of chylomicrons and very low density lipoprotein (VLDL) was accelerated due to a faster plasma hydrolysis of triglycerides by lipoprotein lipase (LPL). Hepatic VLDL and intestinal chylomicron production were not affected. The functional interplay between apoAV and LPL was further investigated by cross-breeding a human LPL transgene with the apoa5 knock-out and the hAPOA5tr to an lpl-deficient background. Increased LPL activity completely normalized hypertriglyceridemia of apoa5-deficient mice; however, overexpression of human apoAV modulated triglyceride levels only slightly when LPL was reduced. To reflect the physiological situation in which LPL is bound to cell surface proteoglycans, we examined hydrolysis in the presence or absence of proteoglycans. Without proteoglycans, apoAV derived either from triglyceride-rich lipoproteins, hAPOA5tr high density lipoprotein, or a recombinant source did not alter the LPL hydrolysis rate. In the presence of proteoglycans, however, apoAV led to a significant and dose-dependent increase in LPL-mediated hydrolysis of VLDL triglycerides. These results were confirmed in cell culture using a proteoglycan-deficient cell line. A direct interaction between LPL and apoAV was found by ligand blotting. It is proposed, that apoAV reduces triglyceride levels by guiding VLDL and chylomicrons to proteoglycan-bound LPL for lipolysis.
Received for publication, October 6, 2004 , and in revised form, February 22, 2005.
* This work was supported in part by German Research Foundation (Deutsche Forschungsgemeinschaft) Grants Me-1507/2-1 and Me-1507/2-4 (to M. M.), the Research Support Fund of the Faculty of Medicine of the University of Hamburg (FFM 2001/16), and Deutsche Forschungsgemeinschaft Grant GRK 336 (to M. M. and J. H.). 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.
** Supported by a fellowship from the Studienstiftung des deutschen Volkes.
To whom correspondence should be addressed: Dept. of Internal Medicine, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Tel.: 49-40-42803-5542; Fax: 49-40-42803-8903; E-mail: merkel{at}uke.uni-hamburg.de.
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