The mechanism of liver carcinogenesis in NASH from the view point of organ crosstalk using tissue specific conditional rescue mice

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07930
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: University of Tsukuba
• Principal Investigator: OKADA Kosuke 筑波大学, 附属病院, 病院講師 (80757526)
• Co-Investigator(Kenkyū-buntansha): 石毛 和紀 筑波大学, 医学医療系, 客員研究員 (20597918) ; 蕨 栄治 筑波大学, 医学医療系, 講師 (70396612) ; 正田 純一 筑波大学, 医学医療系, 教授 (90241827)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: NASH / NASH肝癌 / p62 / Nrf2

Outline of Final Research Achievements

We generated p62 and Nrf2 double knockout (DKO) mice and demonstrated that these mice developed to NASH. And, we found that DKO mice developed severe fibrosis and liver cancer induced by high fat diet. To elucidate the mechanism of liver carcinogenesis in organ crosstalk, we generated tissue specific conditional p62 rescue mice. The rescue of hepatocytes p62 suppressed the development of NASH and reduced the prevalence of liver cancer from 39% to 14%.To evaluate the role of p62 in human NASH and liver cancer, clinical specimens collected by surgery were analyzed by p62 immunohistochemistry. The intensity and lorcalization of p62 associated with hepatic inflammation and fibrosis in non-tumor area, however, did not associate with differentiation and size of liver cancers. p62 in hepatocytes played 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.

Free Research Field

肝臓病学

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，確立された薬物治療も存在しない．本研究は，DKOマウスに高脂肪食を摂餌させるという簡便な方法でヒト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すると考えられる．また，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，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意義が大きい．