Pigment epithelium-derived factor 34-mer peptide prevents liver fibrosis and hepatic stellate cell activation through down-regulation of the PDGF receptor.
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 (PPARγ) 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 PPARγ mRNA and protein in a dose-dependent manner and markedly reduced the level of active β-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 PPARγ suppression was abolished by both the IWR-1 inhibitor and a small interfering RNA (siRNA) targeting β-catenin and the Wnt coreceptor, LRP6. Both PEDF and the 34-mer down-regulated PDGF receptor-α/β expression and blocked the PDGF-induced phosphorylation of Akt and ERK. Moreover, the inhibitory effect on PDGF receptor expression was abolished by PPARγ antagonists and PPARγ 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 PPARγ induction, suppression of Wnt/β-catenin signaling and down-regulation of the PDGF receptor-α/β.
Department of Neurosurgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Republic of China.
Tung-Han
TH
Tsai
Department of Gastroenterology, Mackay Memorial Hospital, Taipai, Republic of China; Mackay Medicine, Nursing and Management College, Taipei, Republic of China.
Shou-Chuan
SC
Shih
Department of Medical Research, Mackay Memorial Hospital, Taipei, Republic of China.
Tsung-Chuan
TC
Ho
Department of Neurosurgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Republic of China.
Hsin-I
HI
Ma
Department of Neurosurgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Republic of China.
Ming-Ying
MY
Liu
Department of Microbiology, School of Medicine, National Taiwan University, Taipei, Republic of China.
Show-Li
SL
Chen
Department of Medical Research, Mackay Memorial Hospital, Taipei, Republic of China.
Yeou-Ping
YP
Tsao
D000818:Animals; D002251:Carbon Tetrachloride; D002460:Cell Line; D015536:Down-Regulation; D005136:Eye Proteins / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000494:pharmacology*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D015843:Serpins / Q000494:pharmacology*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
D002251:Carbon Tetrachloride; D005136:Eye Proteins; D009414:Nerve Growth Factors; D047495:PPAR gamma; D010446:Peptide Fragments; D017479:Receptors, Platelet-Derived Growth Factor; D015843:Serpins; D051176:beta Catenin; D000099174:Pigment Epithelium-Derived Factor; C495268:Ctnnb1 protein, rat