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J. Biol. Chem., Vol. 279, Issue 10, 9030-9036, March 5, 2004

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Endocytosis of Hepatic Lipase and Lipoprotein Lipase into Rat Liver Hepatocytes in Vivo Is Mediated by the Low Density Lipoprotein Receptor-related Protein^*

Marcel Vergés, Andre Bensadoun¶, Joachim Herz||, John D. Belcher**, and Richard J. Havel

From the Cardiovascular Research Institute, University of California, San Francisco, California 94143, the Department of Anatomy and Biochemistry and Biophysics, the ^¶Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, and the ^||Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390

In isolated cell studies, the internalization and degradation of hepatic lipase (HL) has been linked to its binding to the low density lipoprotein receptor-related protein (LRP). We have utilized the receptor-associated protein (RAP), a universal inhibitor of high affinity ligand binding to LRP, to evaluate the participation of LRP in the endocytosis of HL and lipoprotein lipase (LPL). We isolated a total endosome fraction from rat livers after a 30-min infusion of recombinant RAP, administered as a glutathione S-transferase conjugate (GST-RAP). GST-RAP infusion had no effect on the concentration of HL in liver homogenates, but its concentration in blood plasma increased progressively by 20%, and enrichment over homogenate of HL in endosomes was reduced by 50% as compared with infusion of GST alone. The concentrations of LPL in liver and plasma were 1.4 and 0.5%, respectively, those of HL, but endosomal enrichment of the two enzymes was similar (10-fold). GST-RAP infusion had no effect on the concentration of LPL in liver but increased its concentration in blood plasma by 250% and reduced its endosomal enrichment by 95% or greater. GST-RAP infusion also reduced endosomal enrichment of LRP by 40%, but enrichment of several other endocytic receptors was unaffected. Endosomal enrichment of several membrane trafficking proteins associated with the endocytic pathway in hepatocytes was unaffected by GST-RAP with the exception of early endosome endosome antigen 1, which was reduced by 85%. We conclude that HL is partially and LPL almost exclusively taken up into rat hepatocytes after binding to the endocytic receptor LRP.

Received for publication, November 26, 2003 , and in revised form, December 17, 2003.

^* This work was supported in part by National Institutes of Health Grants AI125144, AI36953, HL14850, HL20948, HL63762, and NS43408 and a Wolfgang Paul award from the Humboldt Foundation (to 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.

^** Present address: Dept. of Medicine, University of Minnesota, Minneapolis, MN 55455.

To whom correspondence should be addressed: Cardiovascular Research Institute, University of California, San Francisco, CA 94143-0130. Tel.: 415-476-2226; Fax: 415-502-5658; E-mail: havelr{at}itsa.ucsf.edu.

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