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 |
Research Field |
Gastroenterology
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Research Institution | The University of Tokyo |
Principal Investigator |
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Project Period (FY) |
2013-08-30 – 2015-03-31
|
Project Status |
Completed (Fiscal Year 2014)
|
Budget Amount *help |
¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
|
Keywords | 非アルコール性脂肪肝炎 / 肝細胞癌 / NASH / 肝癌 / ERストレス / 炎症 |
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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Report
(3 results)
Research Products
(5 results)
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[Journal Article] Impact of serum levels of interleukin-6 and adiponectin on all-cause, liver-related, and liver-unrelated mortality in chronic hepatitis C patients.2015
Author(s)
Nakagawa H, Fujiwara N, Tateishi R, Arano T, Nakagomi R, Kondo M, Minami T, Sato M, Uchino K, Enooku K, Asaoka Y, Kondo Y, Shiina S, Yoshida H, Koike K.
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Journal Title
J Gastroenterol Hepatol.
Volume: 30
Issue: 2
Pages: 379-88
DOI
Related Report
Peer Reviewed
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[Journal Article] ER Stress Cooperates with Hypernutrition to Trigger TNF-Dependent Spontaneous HCC Development2014
Author(s)
Nakagawa H, Umemura A, Taniguchi K, Font-Burgada J, Dhar D, Ogata H, Zhong Z, Valasek MA, Seki E, Hidalgo J, Koike K, Kaufman RJ, Karin M.
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Journal Title
Cancer Cell
Volume: 26
Issue: 3
Pages: 331-343
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Loss of liver E-cadherin induces sclerosing cholangitis and promotes carcinogenesis.2014
Author(s)
Nakagawa H, Hikiba Y, Hirata Y, Font-Burgada J, Sakamoto K, Hayakawa Y, Taniguchi K, Umemura A, Kinoshita H, Sakitani K, Nishikawa Y, Hirano K, Ikenoue T, Ijichi H, Dhar D, Shibata W, Akanuma M, Koike K, Karin M, Maeda S.
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Journal Title
Proc Natl Acad Sci U S A.
Volume: 111
Issue: 3
Pages: 1090-1095
DOI
Related Report
Peer Reviewed
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