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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2125.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Phosphatidylinositol-3-Kinase Regulates Scavenger Receptor Class B Type I Subcellular Localization and Selective Lipid Uptake in Hepatocytes

Shoba Shetty; Erik R.M. Eckhardt; Steven R. Post; Deneys R. van der Westhuyzen

From the Graduate Center for Nutritional Sciences (S.S., S.R.P., D.R.v.d.W.), and the Departments of Internal Medicine (S.S., E.R.M.E., D.R.v.d.W.), Molecular and Biomedical Pharmacology (S.R.P.), and Molecular and Cellular Biochemistry (D.R.v.d.W.), University of Kentucky, Lexington.

Correspondence to Deneys R. van der Westhuyzen PhD, Department of Internal Medicine, University of Kentucky, C.T. Wethington Bldg, Rm 541, 900 S Limestone St, Lexington, KY 40536-0200. E-mail dvwest1{at}uky.edu

Objective— The high-density lipoprotein (HDL) receptor scavenger receptor Class B type I (SR-BI) plays a key role in mediating the final step of reverse cholesterol transport. This study examined the possible regulation of hepatic SR-BI by phosphatidylinositol-3-kinase (PI3K), a well known regulator of endocytosis and membrane protein trafficking.

Methods and Results— SR-BI-dependent HDL selective cholesterol ester uptake in human HepG2 hepatoma cells was decreased (&50%) by the PI3K inhibitors wortmannin and LY294002. Insulin increased selective uptake (&30%), and this increase was blocked by PI3K inhibitors. Changes in SR-BI activity could be accounted for by pronounced changes in the subcellular localization and cell surface expression of SR-BI as determined by HDL cell surface binding, receptor biotinylation studies, and confocal fluorescence microscopy of HepG2 cells expressing green fluorescent protein-tagged SR-BI. Thus, under conditions of PI3K activation by insulin, and to a lesser extent by the SR-BI ligand HDL, cell surface expression of SR-BI was promoted, resulting in increased SR-BI-mediated HDL selective lipid uptake.

Conclusion— Our data indicate that PI3K activation stimulates hepatic SR-BI function post-translationally by regulating the subcellular localization of SR-BI in a P13K-dependent manner. Decreased hepatocyte PI3K activity in insulin-resistant states, such as type 2 diabetes, obesity, or metabolic syndrome, may impair reverse cholesterol transport by reducing cell surface expression of SR-BI.

PI3K regulates the cell surface expression of SR-BI and, consequently, selective lipid uptake from HDL. Along with demonstrating a novel post-translational regulation of SR-BI in hepatocytes, this study also suggests the possibility of impaired cholesterol clearance via SR-BI under conditions of decreased PI3K activity seen in insulin resistance.

Key Words: SR-BI • HDL • PI3-kinase • reverse cholesterol transport • insulin resistance

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