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Journal of Lipid Research, Vol. 50, 98-107, January 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

A high-cholesterol diet increases the association between caveolae and insulin receptors in rat liver

Michal Hahn-Obercyger^*, Lutz Graeve and Zecharia Madar^1,*

^* The Hebrew University of Jerusalem, Faculty of Agricultural, Food and Environmental Quality Sciences, Institute of Biochemistry, Food Science and Nutrition, Rehovot, Israel
University of Hehenheim, Institute of Biological Chemistry and Nutrition, Stuttgart, Germany

Published, JLR Papers in Press, August 29, 2008.

This work was supported by Hohenheim foundation grant 0306352.

¹ To whom correspondence should be addressed. e-mail: madar{at}agri.huji.ac.il

Caveolin-1, a component of caveolae, regulates signaling pathway compartmentalization by interacting with tyrosine (Tyr) kinase receptors and their substrates. Perturbations in caveolae lipid composition have been shown in vitro to displace proteins from lipid microdomains, thereby altering their functionality and subsequent downstream signaling. The role of caveolin-1 in insulin receptor (IR) signaling has been widely investigated in vitro mainly in 3T3-L1 adipocyte cells. However, in vivo experiments investigating this connection in liver tissue have not been carried out. The objective of the present study was to investigate the effects of a high-cholesterol diet on caveolin-1 expression and IR localization and activity in the rat liver. Compared with a standard diet, rats fed with diet rich in cholesterol significantly altered liver caveolae by increasing both caveolin-1 (66%, P < 0.05) and caveolin-2 (55%, P < 0.05) expression while caveolin-1 mRNA levels were reduced. Concomitantly, a 25% increase in localization of the caveolae-resident signaling protein IR was observed. The distribution of caveolar and noncaveolar phosphorylated IR was unaffected but insulin-induced IR activation was significantly enhanced following consumption of the high-cholesterol diet (120%, P < 0.001). However, the downstream molecules IRS-1 and Akt have shown impaired activity in cholesterol-fed rats suggesting insulin resistance condition. Insulin stimulation failed to induce Tyr phosphorylation of caveolin-1 in cholesterol-fed rats. These findings suggest a mechanism by which a high-cholesterol diet altered caveolin-1 expression in vivo accompanied by altered IR localization and activity.

Supplementary key words caveolin • insulin signaling • lipid rafts

Abbreviations: IR, insulin receptor; TBST, tris-buffered saline with 0.1% Tween; TC, total cholesterol; TG, triglycerides; Tyr, tyrosine

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