Pigment epithelium-derived factor is an angiogenesis and lipid regulator that activates peroxisome proliferator-activated receptor alpha.
Pigment epithelium-derived factor (PEDF) is an endogenous antiangiogenic protein that also possesses antitumor activity. The mechanisms by which PEDF exerts its actions remains poorly understood. We sought to understand the role of PEDF in hepatocellular carcinoma (HCC), a hypervascular malignancy that has been shown to upregulate enzymes involved in fatty acid synthesis. PEDF expression occurs in two HCC cell lines and is oxygen dependent. Migration studies confirm PEDF's role as an endogenous inhibitor of angiogenesis in HCC cells. Loss of PEDF in an animal model leads to hepatocyte lipid accumulation, proliferation, and cellular atypia. To investigate potential interactions with transcription factors that are involved in fatty acid metabolism and cellular proliferation, we examined PEDF's interaction with PPARalpha in vitro and its functional activity through transactivation assays. We show that PEDF binds to PPARalpha but minimally to PPARgamma. In the presence of the ligand, ciprofibrate, PEDF binding to PPARalpha decreases whereas the presence of troglitazone does not alter PEDF interactions with PPARgamma. Transfection of the PEDF gene in the presence of the PPARalpha/RXR heterodimer demonstrates transcriptional activation of PPARalpha by PEDF. These data show that PEDF regulates lipid metabolism through activation of the transcription factor PPARalpha.
Chung
Chuhan
C
Section of Digestive Disease, Yale University School of Medicine, West Haven, CT, USA.
Doll
Jennifer A
JA
Stellmach
Veronica M
VM
Gonzales
John
J
Surapureddi
Sailesh
S
Cornwell
Mona
M
Reddy
Janardan K
JK
Crawford
Susan E
SE
D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia; D002465:Cell Movement / Q000502:physiology; D002839:Chromans / Q000494:pharmacology; D002995:Clofibric Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology; D005136:Eye Proteins / Q000378:metabolism*; D058607:Fibric Acids; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology; D050356:Lipid Metabolism; D008113:Liver Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000473:pathology*; D009414:Nerve Growth Factors / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D015843:Serpins / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone; D014407:Tumor Cells, Cultured; D000099174:Pigment Epithelium-Derived Factor
D002839:Chromans; D002995:Clofibric Acid; D005136:Eye Proteins; D058607:Fibric Acids; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D009414:Nerve Growth Factors; D047493:PPAR alpha; D047495:PPAR gamma; D015843:Serpins; D045162:Thiazolidinediones; D000077288:Troglitazone; D000099174:Pigment Epithelium-Derived Factor; C019304:ciprofibrate