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J. Biol. Chem., Vol. 279, Issue 3, 2221-2230, January 16, 2004

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Localization of Low Density Lipoprotein Receptor-related Protein 1 to Caveolae in 3T3-L1 Adipocytes in Response to Insulin Treatment^*

Hongyu Zhang, Philip H. Links¶, Johnny K. Ngsee||, Khai Tran, Zheng Cui**, Kerry W. S. Ko, and Zemin Yao

From the Lipoprotein and Atherosclerosis Group, University of Ottawa Heart Institute, Ottawa K1Y 4W7, the Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa K1H 8M5, ^||Ottawa Health Research Institute, Cellular and Molecular Medicine, University of Ottawa, Ottawa K1Y 4E9, Canada, the ^**Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, and Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa K1H 8M5, Canada

The insulin-induced translocation of low density lipoprotein receptor-related protein 1 (LRP1) from intracellular membranes to the cell surface in 3T3-L1 adipocytes was differentiation-dependent and did not occur in 3T3-L1 fibroblasts. Prompted by findings that the plasma membrane of 3T3-L1 adipocytes was rich in caveolae, we determined whether LRP1 became caveolae-associated upon insulin stimulation. The caveolae domain was isolated by the well characterized detergent solubilization and sucrose density ultracentrifugation methodology. Under basal conditions, only a trace amount of LRP1 was caveolae-associated despite the markedly elevated caveolin-1 and caveolae after adipocytic cell differentiation. Upon insulin treatment, the amount of LRP1 associated with caveolae was increased by 4-fold within 10 min, which was blocked completely by pretreatment with wortmannin prior to insulin. The caveolar localization of LRP1 in adipocytes was specific to insulin; treatment with platelet-derived growth factor-bb isoform did not promote but rather decreased caveolar localization of LRP1 below basal levels. The insulin-induced caveolar localization of LRP1 was also observed in 3T3-L1 fibroblasts where translocation of LRP1 from intracellular membranes to the cell surface was absent, suggesting that association of LRP1 with caveolae was achieved, at least in part, through lateral transmigration along the plane of plasma membranes. Immunocytochemistry studies revealed partial co-localization of LRP1 (either endogenous LRP1 or an epitope-tagged minireceptor) with caveolin-1 in cells treated with insulin, which was confirmed by co-immunoprecipitation of LRP1 with caveolin-1 in cells treated with insulin but not platelet-derived growth factor-bb. These results suggest that the localization of LRP1 to caveolae responds selectively to extracellular signals.

Received for publication, September 26, 2003 , and in revised form, October 19, 2003.

^* This work was supported by Grant GR-11471 from the Canadian Institutes for Health 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.

^¶ Recipient of a doctoral scholarship from Canadian Institutes of Health Research and Heart and Stroke Foundation of Canada.

Scientist of Canadian Institutes for Health Research and Career Investigator of the Heart and Stroke Foundation of Canada. To whom correspondence should be addressed. Tel.: 613-798-5555 (ext. 18711); Fax: 613-761-5281; E-mail: zyao{at}ottawaheart.ca.

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