Phosphatidylinositol-3-kinase regulates scavenger receptor class B type I subcellular localization and selective lipid uptake in hepatocytes.
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.


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.
Shetty
Shoba
S
Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY, USA.
Eckhardt
Erik R M
ER
Post
Steven R
SR
van der Westhuyzen
Deneys R
DR
D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D050356:Lipid Metabolism / Q000502:physiology*; D008075:Lipoproteins, HDL / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051122:Scavenger Receptors, Class B / Q000145:classification / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism*; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
D007328:Insulin; D008075:Lipoproteins, HDL; D051122:Scavenger Receptors, Class B; D019869:Phosphatidylinositol 3-Kinases