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 microM 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 [(14)C]cholesteryl esters but only under conditions in which lipogenesis and LD formation are enhanced by treatment with oleic acid. 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
Riikka
R
National Institute for Health and Welfare, University of Helsinki, Helsinki, Finland.
Suchanek
Monika
M
Spandl
Johanna
J
Bäck
Nils
N
Thiele
Christoph
C
Olkkonen
Vesa M
VM
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006888:Hydroxycholesterols / Q000737:chemistry / Q000378:metabolism; D002479:Inclusion Bodies / Q000737:chemistry / Q000378:metabolism; D007653:Ketocholesterols / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry*; D034622:RNA Interference; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D000098825:Oxysterol Binding Proteins
D002352:Carrier Proteins; D006888:Hydroxycholesterols; D007653:Ketocholesterols; D008024:Ligands; D008055:Lipids; C461064:OSBPL2 protein, human; D011987:Receptors, Steroid; D000098825:Oxysterol Binding Proteins; C003585:22-hydroxycholesterol; D002784:Cholesterol; C003001:7-ketocholesterol