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

Authors:
Shetty S, Eckhardt ER, Post SR, van der Westhuyzen DR
In:
Source: Arterioscler Thromb Vasc Biol
Publication Date: (2006)
Issue: 26(9): 2125-31
Research Area:
Cancer Research/Cell Biology
Cells used in publication:
Hep G2
Species: human
Tissue Origin: liver
Platform:
Nucleofectorâ„¢ I/II/2b
Abstract
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 (approximately 50%) by the PI3K inhibitors wortmannin and LY294002. Insulin increased selective uptake (approximately 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. CONCLUSIONS: 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.