| Project/Area Number |
18H03197
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 59040:Nutrition science and health science-related
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| Research Institution | Tokyo Women's Medical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
徳重 克年 東京女子医科大学, 医学部, 教授 (60188729)
山本 雅一 東京女子医科大学, 医学部, 教授 (60220498)
蕨 栄治 筑波大学, 医学医療系, 講師 (70396612)
岡田 浩介 筑波大学, 附属病院, 病院講師 (80757526)
正田 純一 筑波大学, 医学医療系, 教授 (90241827)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
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| Keywords | NASH / 肝癌 / p62 / Nff2 / lipophagy / fatty acid metabolism / 遺伝子改変マウス / 遺伝子レスキューマウス / 脂肪性肝炎 / 脂肪酸代謝 / ミトコンドリア / 肝発癌 / 遺伝子ノックイン / 非アルコール性脂肪性肝炎 |
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| Outline of Final Research Achievements |
p62 and Nrf2 double knock-out (DKO) mice exhibit severe NASH and liver cancers by a high fat feeding. To elucidate the mechanism of liver carcinogenesis associated with organ cross talks, tissue specific conditional p62 rescue mice were generated and analyzed. The p62 gene rescue of hepatocytes suppressed the development of NASH and reduced the prevalence of liver cancer from 39% to 14%. To explore the role of p62 in human NASH and liver cancer, clinical liver specimens collected by surgery were analyzed by p62 immunohistochemistry. The intensity and localization of p62 associated with hepatic inflammation and fibrosis in non-tumor (cirrhosis) area, however, did not associate with differentiation and size of liver cancers.
p62 in hepatocytes was considered to play a protective role against the development of steatohepatitis and liver cancer. Activation of p62 could be a promising target for the prevention and treatment of NASH and liver cancer.
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| Academic Significance and Societal Importance of the Research Achievements |
非アルコール性脂肪性肝炎（NASH）は，単純性脂肪肝から発生し，肝硬変，肝癌へ進行する致死的疾患にも関わらず，その発症機序は未解明であり，NASH進行および肝癌発生を阻止するための薬物治療も確立していない．本研究は，DKOマウスに高脂肪食を摂餌させるという方法でヒトNASHおよび肝癌に類似する新規モデルを作製したことにより，NASH肝発癌のメカニズム解明に寄与出来る．基礎と臨床の両面から，肝細胞のp62がNASHと肝癌に対して防御的な役割を果たすことを見出したことにより，p62が新しいNASHの治療標的と成り得る可能性を示した点で，将来的なNASH治療開発のための研究として意義が大きい．
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