2014 Fiscal Year Final Research Report
Roles of inflammation- and stress-related signaling pathways in NASH-associated hepatocarcinogenesis
| Project/Area Number |
25893042
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Single-year Grants |
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| Research Field |
Gastroenterology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
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| Project Period (FY) |
2013-08-30 – 2015-03-31
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| Keywords | 非アルコール性脂肪肝炎 / 肝細胞癌 |
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| Outline of Final Research Achievements |
This study analyzed the mechanisms of NASH- and obesity-associated hepatocarcinogenesis using new mouse models. Feeding an HFD to MUP-uPA mice resulted in steatohepatitis that closely resembles the pathology of human NASH, eventually leading to spontaneous development of HCC. In this mouse model, the vicious cycle of ER stress and hypernutrition synergistically aggravates lipid accumulation in the liver via SREBP activation, which leads to excess oxidative stress, ballooning degeneration, and susceptibility to lipotoxic cell death. In parallel, increased TNFα expression during this process further accelerates NASH and HCC development in a TNF receptor 1-IKK-NF-κB-dependent manner. Reducing ER stress using chemical chaperones significantly improved liver pathology, suggesting that interrupting this vicious cycle might be a promising therapeutic target for NASH and HCC.
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| Free Research Field |
肝臓病学
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