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J. Biol. Chem., Vol. 279, Issue 38, 39348-39357, September 17, 2004

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Effect of Insulin on Caveolin-enriched Membrane Domains in Rat Liver^*

Alejandro Balbis, Gerardo Baquiran, Catherine Mounier, and Barry I. Posner

From the Polypeptide Hormone Laboratory, Faculty of Medicine, McGill University, 3640 University St., Suite W315, Montreal, Quebec H3A 2B2, Canada

Compartmentalization of signaling molecules may explain, at least in part, how insulin or growth factors achieve specificity. Caveolae/rafts are specialized lipid compartments that have been implicated in insulin signaling. In the present study, we investigated the role of caveolin-enriched membrane domains (CMD) in mediating insulin signaling in rat liver. We report the existence of at least two different populations of CMD in rat liver plasma membranes (PM). One population is soluble in Triton X-100 and seems to be constitutively associated with cytoskeletal elements. The other population of CMD is located in a membrane compartment insoluble in Triton X-100 with light buoyant density and is hence designated CMD/rafts. We found evidence of rapid actin reorganization in rat liver PM in response to insulin, along with the association of CMD/rafts and insulin signaling molecules with a cell fraction enriched in cytoskeletal elements. The presence of CMD in liver parenchyma cells was confirmed by the presence of caveolin-1 in primary rat hepatocyte cultures. Cholesterol depletion, effected by incubating hepatocytes with 2 mM methyl--cyclodextrin, did not permeabilize the cells or interfere with clathrin-dependent internalization. However, at this concentration, methyl--cyclodextrin perturbed CMD of hepatocyte PM and inhibited insulin-induced Akt activation and glycogen synthesis but did not affect insulin-induced insulin receptor kinase tyrosine phosphorylation. These events, together with the presence of a functional insulin receptor in CMD of rat liver PM, suggest that insulin signaling is influenced by the interaction of caveolae with cytoskeletal elements in liver.

Received for publication, April 16, 2004 , and in revised form, June 25, 2004.

^* This work was supported by the Canadian Institutes for Health Research and the National Cancer Institute of Canada. We appreciate the continuing generosity of the Cleghorn Fund at McGill University, and the Maurice Pollack Foundation of Montreal. 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.

To whom correspondence should be addressed. Tel.: 514-398-4101; Fax: 514-398-3923; E-mail: barry.posner{at}staff.mcgill.ca.

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