2020 Fiscal Year Final Research Report

The characteristic changes of Kupffer cells and hepatic stellate cells after menopause increase the risk of NASH and liver cancer.

Research Project

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Project/Area Number	18H03172
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 59040:Nutrition science and health science-related
Research Institution	University of Tsukuba
Principal Investigator	Suzuyki Hideo 筑波大学, 医学医療系, 准教授 (00400672)
Co-Investigator(Kenkyū-buntansha)	柳川徹筑波大学, 医学医療系, 教授 (10312852) 磯辺智範筑波大学, 医学医療系, 教授 (70383643) 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)
Project Period (FY)	2018-04-01 – 2021-03-31
Keywords	NASH / 性差 / estradiol / LPS
Outline of Final Research Achievements	Gender and menopause influence the severity and development of nonalcoholic steatohepatitis (NASH). Male p62 and Nrf2 double-knockout (DKO) mice exhibit NASH caused by overload of lipopolysaccharide (LPS) into the liver, and potentiation of the inflammatory response in Kupffer cells. Phenotypic changes of NASH in DKO mice were compared in terms of gender differences. Compared with DKO male mice, DKO female mice exhibited later onset of NASH with milder severity of hepatic inflammation and fibrosis. Serum estradiol was higher in female than male mice, and decreasing until 50 weeks of age. Fecal and serum LPS were lower in female mice than male mice, and inflammatory signaling in the liver was attenuated in female. The composition of intestinal microbiota in female mice was different from male mice. Gender differences were observed for the development of NASH in DKO mice. Low-grade inflammatory hit in the liver under high estradiol may be attributable to the milder NASH in female mice.
Free Research Field	消化器内科
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．加えて，NASHの進展および重症度は性差や閉経により影響されることが疫学調査で明らかとなってきた．そのメカニズムとして性ホルモンの関与が強く疑われるが，その詳細の解明は臨床研究では限界がある．本研究は，ヒトNASH病態に類似する新規モデルマウスであるDKOマウスを用いて，NASH病態の性差がestradiolによる腸内細菌叢におけるLPS産生や肝炎症シグナルへの修飾に起因することを実験的に明らかにした点で意義が大きい．