Pigment Epithelium-derived Factor is an Angiogenesis and Lipid Regulator that Activates Peroxisome Proliferator-activated Receptor α
Purchase on Springer.com
$29.95 / €24.95 / £19.95*
* Final gross prices may vary according to local VAT.
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 PPARα in vitro and its functional activity through transactivation assays. We show that PEDF binds to PPARα but minimally to PPARγ. In the presence of the ligand, ciprofibrate, PEDF binding to PPARα decreases whereas the presence of troglitazone does not alter PEDF interactions with PPARγ. Transfection of the PEDF gene in the presence of the PPARα/RXR heterodimer demonstrates transcriptional activation of PPARα by PEDF. These data show that PEDF regulates lipid metabolism through activation of the transcription factor PPARα.
- Yahagi N, Shimano H, Hasegawa K, et al. (2005) Co-ordinate activation of lipogenic enzymes in hepatocellular carcinoma. Eur J Cancer;41:1316–22. CrossRef
- Tombran-Tink J, Barnstable CJ (2003) PEDF: a multifaceted neurotrophic factor. Nat Rev Neuro;4:628–36. CrossRef
- Chader GJ (2001) PEDF: raising both hopes and questions in controlling angiogenesis. Proc Natl Acad Sci USA;98:2122–44. CrossRef
- Steele FR, Chader GJ, Johnson LV, et al. (1993) Pigment epithelium-derived factor: neurotrophic activity and identification as a member of the serine protease inhibitor gene family. Proc Natl Acad Sci USA;15:1526–30. CrossRef
- Becerra SP (1997) Structure-function studies on PEDF. A noninhibitory serpin with neurotrophic activity. Adv Exp Med Biol;425:223–37.
- Karakousis PC, John SK, Behling KC, et al. (2001) Localization of pigment epithelium derived factor (PEDF) in developing and adult human ocular tissues. Mol Vis;7:153–63.
- Ramirez-Castillejo C, Sanchez-Sanchez F, Andreu-Agullo C, et al. (2006) Pigment epithelium-derived factor is a niche signal for neural stem cell renewal. Nat Neuro;9:331–39. CrossRef
- Dawson DW, Volpert OV, Gillis P, et al. (1999) Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science;285:245–48. CrossRef
- Aoyama, T, Peters, J, et al. (1998) Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARα). J Biol Chem;273:5678–84. CrossRef
- Reddy JK (2004) Peroxisome proliferators and peroxisome proliferator-activated receptor alpha: biotic and xenobiotic sensing. Am J Pathol;164:2305–21.
- Doll JA, Stellmach VM, Bouck NP, et al. (2003) Pigment epithelium-derived factor regulates the vasculature and mass of the prostate and pancreas. Nat Med 2003;9:774–80. CrossRef
- Hostetler, H, Petrescu, AD, et al. (2005) Peroxisome proliferator-activated receptor alpha interacts with high affinity and is conformationally responsive to endogenous ligands. J Biol Chem;280:18667–82. CrossRef
- Pignolo, RJ, Francis MK, et al. (2003) Putative role for EPC-1/PEDF in the G0 growth arrest of human diploid fibroblasts. J Cell Physiol;195:12–20. CrossRef
- Crawford SE, Stellmach VM, et al. (2001) epithelium-derived factor (PEDF) in neuroblastoma: a multifunctional mediator of Schwann cell antitumor activity. J Cell Sci;114:4421–8.
- Pigment Epithelium-derived Factor is an Angiogenesis and Lipid Regulator that Activates Peroxisome Proliferator-activated Receptor α
- Book Title
- Hormonal Carcinogenesis V
- pp 591-597
- Print ISBN
- Online ISBN
- Series Title
- Advances in Experimental Medicine and Biology
- Series Volume
- Series ISSN
- Springer New York
- Copyright Holder
- Springer New York
- Additional Links
- Industry Sectors
- eBook Packages
- Editor Affiliations
- 1. Medical Center Department of Pharmacology, University of Kansas
- 2. Division of Cancer Biology, National Cancer Institute
- 3. Hormone and Cancer Unit, U540, Montpellier University and INSERM
- 4. Department of Cell Biology, Montpellier University 1-INSERM, U540 Hospital Arnaud de Villeneuve
- Author Affiliations
- 5. Section of Digestive Diseases, Yale University School of Medicine, West Haven, CT, USA
- 6. Feinberg School of Medicine Department of Pathology, Northwestern University, Chicago, IL, USA
To view the rest of this content please follow the download PDF link above.