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Selective deletion of hepatocyte platelet-derived growth factor receptor α and development of liver fibrosis in mice

Authors
 Beom Jin Lim  ;  Woon-Kyu Lee  ;  Hyun Woong Lee  ;  Kwan Sik Lee  ;  Ja Kyung Kim  ;  Hye Young Chang  ;  Jung Il Lee 
Citation
 Cell Communication and Signaling, Vol.16(1) : 93, 2018 
Journal Title
 Cell Communication and Signaling 
Issue Date
2018
Keywords
Hepatic stellate cell ; Hepatocyte ; Liver cirrhosis ; Liver fibrosis ; Platelet-derived growth factor receptor α
Abstract
BACKGROUND: Platelet-derived growth factor receptor α (PDGFRα) expression is increased in activated hepatic stellate cells (HSCs) in cirrhotic liver, while normal hepatocytes express PDGFRα at a negligible level. However, cancerous hepatocytes may show upregulation of PDGFRα, and hepatocellular carcinoma is preceded by chronic liver injury. The role of PDGFRα in non-cancerous hepatocytes and liver fibrosis is unclear. We hypothesized that upon liver injury, PDGFRα 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 PDGFRα expression. Conditional knock-out (KO) C57BL/6 mice, in which PDGFRα 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) (PDGFRα or control) and co-cultured with LX2 cells. RESULTS: PDGFRα expression was increased in hepatocytes from fibrotic livers compared to normal livers. Conditional PDGFRα 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)-β and Smad2/3, this was compensated for by increased expression of inhibitory Smad7. LX2 cells co-cultured with PDGFRα siRNA-infected Hep3B cells showed decreased PDGFRα, α smooth muscle actin, collagen α1(I), TGFβ, and Smad2/3 expression. LX2/PDGFRα-deleted hepatocyte co-culture medium showed decreased PDGF-BB and PDGF-CC levels. CONCLUSIONS: Deletion of PDGFRα in hepatocytes attenuated the upregulation of PDGFRα in HSCs after TAA treatment, resulting in decreased liver fibrosis and HSC activation. This suggests that in the event of chronic liver injury, PDGFRα in hepatocytes plays an important role in liver fibrosis by affecting PDGFRα expression in HSCs.
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DOI
10.1186/s12964-018-0306-2
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
김자경(Kim, Ja Kyung) ORCID logo https://orcid.org/0000-0001-5025-6846
이관식(Lee, Kwan Sik) ORCID logo https://orcid.org/0000-0002-3672-1198
이정일(Lee, Jung Il) ORCID logo https://orcid.org/0000-0002-0142-1398
이현웅(Lee, Hyun Woong) ORCID logo https://orcid.org/0000-0002-6958-3035
임범진(Lim, Beom Jin) ORCID logo https://orcid.org/0000-0003-2856-0133
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/166824
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