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2014 Fiscal Year Final Research Report

Roles of inflammation- and stress-related signaling pathways in NASH-associated hepatocarcinogenesis

Research Project

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Project/Area Number 25893042
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeSingle-year Grants
Research Field Gastroenterology
Research InstitutionThe University of Tokyo

Principal Investigator

HAYATO NAKAGAWA  東京大学, 医学部附属病院, 助教 (00555609)

Project Period (FY) 2013-08-30 – 2015-03-31
Keywords非アルコール性脂肪肝炎 / 肝細胞癌
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.

Free Research Field

肝臓病学

URL: 

Published: 2016-06-03  

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