OSBP-related protein 2 is a sterol receptor on lipid droplets that regulates the metabolism of neutral lipids

Oxysterol binding protein-related protein 2 (ORP2) is a member of the oxysterol binding protein family, previously shown to bind 25-hydroxycholesterol and implicated in cellular cholesterol metabolism. We show here that ORP2 also binds 22(R)-hydroxycholesterol [22(R)OHC], 7-ketocholesterol, and cholesterol, with 22(R) OHC being the highest affinity ligand of ORP2 (K-d 1.4 x 10(-8) M). We report the localization of ORP2 on cytoplasmic lipid droplets (LDs) and its function in neutral lipid metabolism using the human A431 cell line as a model. The ORP2 LD association depends on sterol binding: Treatment with 5 mu M 22(R) OHC inhibits the LD association, while a mutant defective in sterol binding is constitutively LD bound. Silencing of ORP2 using RNA interference slows down cellular triglyceride hydrolysis. Furthermore, ORP2 silencing increases the amount of [C-14] cholesteryl esters but only under conditions in which lipogenesis and LD formation are enhanced by treatment with oleic acid.glr The results identify ORP2 as a sterol receptor present on LD and provide evidence for its role in the regulation of neutral lipid metabolism, possibly as a factor that integrates the cellular metabolism of triglycerides with that of cholesterol.-Hynynen, R., M. Suchanek, J. Spandl, N. Back, C. Thiele, and V. M. Olkkonen. OSBP-related protein 2 is a sterol receptor on lipid droplets that regulates the metabolism of neutral lipids. J. Lipid Res. 2009. 50: 1305-1315.