%0 Journal Article
%T Pigment Epithelium-Derived Factor 34-mer Peptide Prevents Liver Fibrosis and Hepatic Stellate Cell Activation through Down-Regulation of the PDGF Receptor
%A Tung-Han Tsai
%A Shou-Chuan Shih
%A Tsung-Chuan Ho
%A Hsin-I Ma
%A Ming-Ying Liu
%A Show-Li Chen
%A Yeou-Ping Tsao
%J PLOS ONE
%D 2014
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0095443
%X Pigment epithelium-derived factor (PEDF) has been shown previously to prevent liver fibrosis and hepatic stellate cell (HSC) activation. By investigating the functional domains in PEDF, we identified a 34-mer peptide (residues Asp44-Asn77) that harbors the same function as the full-length PEDF protein. Not only did the 34-mer suppress the development of fibrosis in carbon tetrachloride (CCl4)-treated mouse liver but it also upregulated peroxisome proliferator-activated receptor-gamma (PPAR¦Ã) expression in HSCs in vivo. Platelet-derived growth factor (PDGF) plays a crucial role on the process of HSC activation in response to liver damage. The 34-mer suppressed PDGF-induced cell proliferation and expression of myofibroblastic marker proteins in primary rat HSC culture, increased the levels of PPAR¦Ã mRNA and protein in a dose-dependent manner and markedly reduced the level of active ¦Â-catenin protein, an HSC activating factor, in HSC-T6 cells. Similarly, IWR-1, an inhibitor of the Wnt response, displayed the same effect as the 34-mer in preventing HSC-T6 activation. The Wnt signaling-mediated PPAR¦Ã suppression was abolished by both the IWR-1 inhibitor and a small interfering RNA (siRNA) targeting ¦Â-catenin and the Wnt coreceptor, LRP6. Both PEDF and the 34-mer down-regulated PDGF receptor-¦Á/¦Â expression and blocked the PDGF-induced phosphorylation of Akt and ERK. Moreover, the inhibitory effect on PDGF receptor expression was abolished by PPAR¦Ã antagonists and PPAR¦Ã siRNA. Our observations indicate that the PEDF-derived 34-mer peptide can mimic PEDF in attenuating HSC activation. Investigation of this 34-mer peptide led to the identification of a signaling mechanism involving PPAR¦Ã induction, suppression of Wnt/¦Â-catenin signaling and down-regulation of the PDGF receptor-¦Á/¦Â.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0095443