Investigation of a novel mechanism of NASH pathogenesis focused on bile acid transporters

• Project/Area Number: 20K17014
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Okushin Kazuya 東京大学, 医学部附属病院, 助教 (40753918)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 胆汁酸トランスポーター / bile salt export pump / Gut-Liver axis / 腸内細菌叢 / 非アルコール性脂肪肝炎 / 胆汁酸 / BSEP / MRP2 / 網羅的遺伝子発現解析 / ノックアウトマウス / 非アルコール性脂肪性肝疾患 / 非アルコール性脂肪性肝炎

Outline of Research at the Start

非アルコール性脂肪性肝疾患（NAFLD）・非アルコール性脂肪性肝炎（NASH）は急増しており、その病態解明と治療法の確立は喫緊の課題である。
これまでにNAFLDの病期進行と、肝内からの胆汁酸排出を司るトランスポーターBSEPの発現が負の相関を示すことを明らかとしてきた。
BSEPがNASH進行に関与するメカニズムの解明を目的として、BSEPの発現を抑制したマウスモデルに高脂肪食を摂取させ、肝臓・腸管・血清といった全身における胆汁酸分画の変化、さらには胆汁酸の代謝に重要な役割を果たす腸内細菌叢の変化を明らかとすることで、NAFLD・NASHの病態に加え、肝臓と腸管の相互作用の解明に寄与したい。

Outline of Final Research Achievements

To elucidate the mechanisms of non-alcoholic steatohepatitis, a mouse model was investigated in which the expression of the bile acid transporter bile salt export pump (BSEP), which is expressed only in the liver, was suppressed. When the mice were fed a high-fat diet, they presented reduced body weight gain and liver steatosis, as well as changes in the expressions of a wide range of metabolism-related genes in the liver and intestinal tract. Furthermore, characteristic changes in the gut microbiota were also observed. These results suggest that BSEP plays an important role in the Gut-Liver axis, which is a functional link among the liver, the intestinal tract, and all the organs in the body.

Academic Significance and Societal Importance of the Research Achievements

非アルコール性脂肪肝炎は肝臓のみならず、糖尿病や大血管イベントにも関与が示唆される重大な疾患であるが、その病態は未だに不明な点が多く、有効な治療は確立していない。
本研究成果は、胆汁酸トランスポーターであるbile salt export pump (BSEP)が、肝臓における胆汁酸代謝のみならず、腸管や腸内細菌叢、そして全身まで影響を及ぼすことを示した重要な知見と考えられる。
BSEPがこれらの変化を生じる詳細なメカニズムの解明は、科学的に重要な知見であるのみならず、BSEPを標的として非アルコール性脂肪肝炎に加えて全身の代謝性疾患の病態解明および治療法の開発に寄与することが期待される。

Research Products

• [Journal Article] Triglyceride level and soft drink consumption predict nonalcoholic fatty liver disease in nonobese male adolescents (2023)
  • Author(s): Kado Akira、Inoue Yukiko、Moriya Kyoji、Tsutsumi Takeya、Ikeuchi Kazuhiko、Okushin Kazuya、Yotsuyanagi Hiroshi、Koike Kazuhiko、Fujishiro Mitsuhiro
  • Journal Title: Hepatology Research Volume: - Issue: 6 Pages: 497-510
  • DOI: 10.1111/hepr.13889
  • Peer Reviewed
• [Journal Article] Current status of primary liver cancer and decompensated cirrhosis in Japan: launch of a nationwide registry for advanced liver diseases (REAL) (2022)
  • Author(s): Okushin Kazuya、Tateishi Ryosuke、Takahashi Arata、Uchino Koji、Nakagomi Ryo、Nakatsuka Takuma、Minami Tatsuya、Sato Masaya、Fujishiro Mitsuhiro、Hasegawa Kiyoshi、Eguchi Yuichiro、Kanto Tatsuya、Kubo Shoji、Yoshiji Hitoshi、Miyata Hiroaki、Izumi Namiki、Kudo Masatoshi、Koike Kazuhiko
  • Journal Title: Journal of Gastroenterology Volume: 57 Issue: 8 Pages: 587-597
  • DOI: 10.1007/s00535-022-01893-5
  • Peer Reviewed
• [Journal Article] Fibrosis-4 index efficiently predicts chronic hepatitis and liver cirrhosis development based on a large-scale data of general population in Japan (2022)
  • Author(s): Yamamichi Nobutake、Shimamoto Takeshi、Okushin Kazuya、Nishikawa Takako、Matsuzaki Hirotaka、Yakabi Seiichi、Takahashi Mami、Wada Ryoichi、Koike Kazuhiko、Fujishiro Mitsuhiro
  • Journal Title: Scientific Reports Volume: 12 Issue: 1
  • DOI: 10.1038/s41598-022-24910-2
  • Peer Reviewed / Open Access
• [Journal Article] Gender-specific factors contributing to visceral obesity including the sleep-obesity relationship: a large-scale cross-sectional study from East Asia (2022)
  • Author(s): Saito Katsuki、Shimamoto Takeshi、Takahashi Yu、Okushin Kazuya、Takahashi Mami、Masuda Yukari、Nishikawa Takako、Kakushima Naomi、Wada Ryoichi、Yamamichi Nobutake
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 20318-20318
  • DOI: 10.1038/s41598-022-24863-6
  • Peer Reviewed / Open Access
• [Journal Article] Prevalence of HIV infection among non-elderly individuals with hepatitis C in Japan: a population-based cohort study using a health insurance claim data (2022)
  • Author(s): Ikeuchi Kazuhiko、Okushin Kazuya、Saito Makoto、Adachi Eisuke、Tsutsumi Takeya、Takura Tomoyuki、Yotsuyanagi Hiroshi
  • Journal Title: BMC Infectious Diseases Volume: 22 Issue: 1 Pages: 167-167
  • DOI: 10.1186/s12879-022-07152-5
  • Peer Reviewed / Open Access
• [Journal Article] HBx-induced degradation of Smc5/6 complex impairs homologous recombination-mediated repair of damaged DNA. (2022)
  • Author(s): Sekiba K, Otsuka M, Funato K, Miyakawa Y, Tanaka E, Seimiya T, Yamagami M, Tsutsumi T, Okushin K, Miyakawa K, Ryo A, Koike K.
  • Journal Title: J Hepatol. Volume: 76 Issue: 1 Pages: 53-62
  • DOI: 10.1016/j.jhep.2021.08.010
  • Peer Reviewed / Open Access
• [Journal Article] Change in hepatitis C virus positivity among needle-stick injury source patients: a 10-year experience in a Japanese tertiary hospital (2021)
  • Author(s): Okushin Kazuya、Suzuki Rie、Tsutsumi Takeya、Okamoto Koh、Ikeuchi Kazuhiko、Kado Akira、Minatsuki Chihiro、Minami-Kobayashi Yuka、Satoh Nobuhiko、Ikeda Mahoko、Harada Sohei、Enooku Kenichiro、Fujinaga Hidetaka、Yotsuyanagi Hiroshi、Koike Kazuhiko、Moriya Kyoji
  • Journal Title: BMC Infectious Diseases Volume: 21 Issue: 1 Pages: 399-399
  • DOI: 10.1186/s12879-021-06117-4
  • Peer Reviewed / Open Access
• [Journal Article] Change in hepatitis C virus positivity among needle-stick injury source patients: A 10-year experience in a Japanese tertiary hospital. (2021)
  • Author(s): Kazuya Okushin, Rie Suzuki, Takeya Tsutsumi, Koh Okamoto, Kazuhiko Ikeuchi, Akira Kado, Chihiro Minatsuki, Yuka Minami-Kobayashi, Nobuhiko Satoh, Mahoko Ikeda, Sohei Harada, Kenichiro Enooku, Hidetaka Fujinaga, Hiroshi Yotsuyanagi, Kazuhiko Koike, and Kyoji Moriya
  • Journal Title: BMC Infectious Diseases Volume: -
• [Journal Article] Heterozygous knockout of Bile salt export pump ameliorates liver steatosis in mice fed a high-fat diet (2020)
  • Author(s): Okushin Kazuya、Tsutsumi Takeya、Ikeuchi Kazuhiko、Kado Akira、Enooku Kenichiro、Fujinaga Hidetaka、Yamauchi Naoko、Ushiku Tetsuo、Moriya Kyoji、Yotsuyanagi Hiroshi、Koike Kazuhiko
  • Journal Title: PLOS ONE Volume: 15 Issue: 8 Pages: e0234750-e0234750
  • DOI: 10.1371/journal.pone.0234750
  • Peer Reviewed / Open Access
• [Presentation] 胆汁酸トランスポーターBSEPヘテロノックアウトマウスの腸内細菌叢は高脂肪食による肝脂肪化に抑制的作用を有する可能性がある (2022)
  • Author(s): 奥新和也, 堤武也, 池内和彦, 門輝, 藤永秀剛, 森屋恭爾, 四柳宏, 小池和彦, 藤城光弘
  • Organizer: 第8回肝臓と糖尿病・代謝研究会
• [Presentation] CURRENT STATUS OF PRIMARY LIVER CANCER AND DECOMPENSATED CIRRHOSIS IN JAPAN: LAUNCH OF A NATIONWIDE REGISTRY (2021)
  • Author(s): Kazuya Okushin, Ryosuke Tateishi, Arata Takahashi, Koji Uchino, Ryo Nakagomi, Kiyoshi Hasegawa, Yuichiro Eguchi, Tatsuya Kanto, Shoji Kubo, Hitoshi Yoshiji, Hiroaki Miyata, Namiki Izumi, Masatoshi Kudo, Kazuhiko Koike, et al.
  • Organizer: American Association for the Study of Liver Diseases The Liver Meeting 2021
  • Int'l Joint Research
• [Presentation] Current treatment selection for primary liver cancer in Japan -Real-world data from a nationwide registry based on multiple hospitalizations- (2021)
  • Author(s): Kazuya Okushin, Ryosuke Tateishi, Arata Takahashi, Koji Uchino, Ryo Nakagomi, Kiyoshi Hasegawa, Yuichiro Eguchi, Tatsuya Kanto, Shoji Kubo, Hitoshi Yoshiji, Hiroaki Miyata, Namiki Izumi, Masatoshi Kudo, and Kazuhiko Koike
  • Organizer: JSH International Liver Conference
  • Int'l Joint Research
• [Presentation] Diagnostic approach of flow cytometry to identify nonalcoholic steatohepatitis with overlapping autoimmune hepatitis in differential patterns of peripheral lymphocytes (2021)
  • Author(s): Kado A, Tsutsumi T, Ikeuchi K, Okushin K, Enooku K, Fujinaga H, Moriya K, Yotsuyanagi H, Koike K.
  • Organizer: American Association for the Study of Liver Diseases The Liver Meeting 2021
  • Int'l Joint Research
• [Presentation] 末梢血リンパ球比率を用いた自己免疫性肝炎合併を含む非アルコール性脂肪肝炎の診断アプローチ (2021)
  • Author(s): 門 輝, 奥新 和也, 榎奥 健一郎, 藤永 秀剛, 堤 武也, 森屋 恭爾, 四柳 宏, 小池 和彦
  • Organizer: 第25回日本肝臓学会大会
• [Presentation] 胆汁酸トランスポーターBSEPのヘテロノックアウトは高脂肪食摂取マウスの肝脂肪化に対して抑制的作用を有する (2020)
  • Author(s): 奥新和也、堤武也、小池和彦
  • Organizer: 第106回日本消化器病学会総会