| First Author | Lim BJ | Year | 2018 |
| Journal | Cell Commun Signal | Volume | 16 |
| Issue | 1 | Pages | 93 |
| PubMed ID | 30509307 | Mgi Jnum | J:281701 |
| Mgi Id | MGI:6363830 | Doi | 10.1186/s12964-018-0306-2 |
| Citation | Lim BJ, et al. (2018) Selective deletion of hepatocyte platelet-derived growth factor receptor alpha and development of liver fibrosis in mice. Cell Commun Signal 16(1):93 |
| abstractText | BACKGROUND: Platelet-derived growth factor receptor alpha (PDGFRalpha) expression is increased in activated hepatic stellate cells (HSCs) in cirrhotic liver, while normal hepatocytes express PDGFRalpha at a negligible level. However, cancerous hepatocytes may show upregulation of PDGFRalpha, and hepatocellular carcinoma is preceded by chronic liver injury. The role of PDGFRalpha in non-cancerous hepatocytes and liver fibrosis is unclear. We hypothesized that upon liver injury, PDGFRalpha in insulted hepatocytes contributes to liver fibrosis by facilitating intercellular crosstalk between hepatocytes and HSCs. METHODS: Hepatocytes were isolated from normal and thioacetamide (TAA)-induced cirrhotic livers for assessment of PDGFRalpha expression. Conditional knock-out (KO) C57BL/6 mice, in which PDGFRalpha was selectively deleted in hepatocytes, were generated. Liver fibrosis was induced by injecting TAA for 8 weeks. Hep3B cells were transfected with a small interfering RNA (siRNA) (PDGFRalpha or control) and co-cultured with LX2 cells. RESULTS: PDGFRalpha expression was increased in hepatocytes from fibrotic livers compared to normal livers. Conditional PDGFRalpha KO mice had attenuated TAA-induced liver fibrosis with decreased HSC activation and proliferation. Immunoblot analyses revealed decreased expression of phospho-p44/42 MAPK in TAA-treated KO mice; these mice also showed almost complete suppression of the upregulation of mouse double minute 2. Although KO mice exhibited increased expression of transforming growth factor (TGF)-beta and Smad2/3, this was compensated for by increased expression of inhibitory Smad7. LX2 cells co-cultured with PDGFRalpha siRNA-infected Hep3B cells showed decreased PDGFRalpha, alpha smooth muscle actin, collagen alpha1(I), TGFbeta, and Smad2/3 expression. LX2/PDGFRalpha-deleted hepatocyte co-culture medium showed decreased PDGF-BB and PDGF-CC levels. CONCLUSIONS: Deletion of PDGFRalpha in hepatocytes attenuated the upregulation of PDGFRalpha in HSCs after TAA treatment, resulting in decreased liver fibrosis and HSC activation. This suggests that in the event of chronic liver injury, PDGFRalpha in hepatocytes plays an important role in liver fibrosis by affecting PDGFRalpha expression in HSCs. |
