| Project/Area Number |
18H03172
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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 | University of Tsukuba |
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Principal Investigator |
Suzuyki Hideo 筑波大学, 医学医療系, 准教授 (00400672)
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| 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)
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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 |
¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
Fiscal Year 2020: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2018: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
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| Keywords | NASH / 性差 / estradiol / LPS / p62 / Nrf2 / 遺伝子改変マウス / 女性ホルモン / 脂肪性肝炎 / 閉経 / Kupffer細胞 / エストロゲン / サルコペニア / Kupffer細胞機能 / サルコペニア肥満 / 非アルコール性脂肪性肝炎 / 肝癌 / 肝星細胞 |
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| 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.
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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，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．
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