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The role of ILDR2 in biomembrane phospholipids and hepatic steatosis

Research Project

Project/Area Number 20K08914
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54040:Metabolism and endocrinology-related
Research InstitutionJichi Medical University

Principal Investigator

Watanabe Kazuhisa  自治医科大学, 医学部, 講師 (60724416)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsILDR2 / 脂肪肝 / リン脂質 / 肝線維化 / 肝硬変
Outline of Research at the Start

脂肪肝は2型糖尿病の重要なリスク因子に留まらず、メタボリックシンドロームと相まった脂肪肝炎からの肝線維化は動脈硬化疾患を増悪させるため、有効な治療法の開発が強く求められている。我々は肥満マウスを用いたポジショナルクローニング法により新規糖尿病感受性遺伝子Ildr2を同定し、ILDR2が脂肪肝発症に重要な因子であることを見出した。本研究では、ILDR2の基礎的な機能の解明を手掛かりに、脂肪肝からの肝線維化進行機序を解明する。

Outline of Final Research Achievements

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes and increases the risk for liver cirrhosis and cancer. A diabetes susceptibility gene, Ildr2, encodes a transmembrane protein localized to the ER membrane whose physiological functions are unknown. We previously identified ILDR2 interaction protein, MBOAT7, which mediates acyl-chain remodeling of phosphatidylinositols (PIs). We hypothesized that ILDR2 may influence hepatic Pl composition in NAFLD. In LKO-ILDR2 mice fed on the choline-deficient amino acid-defined high fat diet (CDAHFD) compared to AAV-GFP injected Ildr2 floxed (GFP-flox) mice fed on the CDAHFD, liver triglyceride content was significantly increased by LKO-ILDR2 mice compared to GFP-flox mice, hepatic PI was significantly increased. Hepatic PI was significantly decreased in OX-ILDR2 mice. Manipulation of hepatic ILDR2 expression is associated with changes in PI molecular species in the liver.

Academic Significance and Societal Importance of the Research Achievements

脂肪肝は2型糖尿病の重要なリスク因子に留まらず、メタボリックシンドロームと相まった脂肪肝炎からの肝線維化は動脈硬化疾患を増悪させるため、有効な治療法の開発が強く求められている。我々はILDR2の局在や結合タンパク質の同定、さらにノックアウトマウスを解析することにより個体レベルでのILDR2の意義と脂肪肝における影響を明らかにした。この研究過程で、ILDR2が肝臓中リン脂質の質的変化に関与し、脂肪肝発症や肝線維化の進展に関与することを示した。脂肪肝の有効な治療法はないため、ILDR2の機能解明は脂肪肝の治療法開発の分子基盤になると期待される。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (12 results)

All 2023 2022 2021 2020 Other

All Int'l Joint Research (3 results) Journal Article (8 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 8 results,  Open Access: 7 results) Presentation (1 results)

  • [Int'l Joint Research] Columbia University(米国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] Columbia University(米国)

    • Related Report
      2021 Research-status Report
  • [Int'l Joint Research] Columbia University(米国)

    • Related Report
      2020 Research-status Report
  • [Journal Article] Lack of GPR180 ameliorates hepatic lipid depot via downregulation of mTORC1 signaling.2023

    • Author(s)
      Yoshida K, Yokota K, Watanabe K, Tsuda H, Matsumoto A, Mizukami H, Iwamoto S.
    • Journal Title

      Sci Rep

      Volume: 13 Issue: 1 Pages: 1843-1843

    • DOI

      10.1038/s41598-023-29135-5

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] KBTBD11, encoding a novel PPARγ target gene, is involved in NFATc1 proteolysis by interacting with HSC70 and HSP602022

    • Author(s)
      Watanabe Kazuhisa、Matsumoto Ayumi、Tsuda Hidetoshi、Iwamoto Sadahiko
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1 Pages: 20273-20273

    • DOI

      10.1038/s41598-022-24929-5

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A case of congenital fiber‐type disproportion syndrome presenting dilated cardiomyopathy with <i>ACTA1</i> mutation2022

    • Author(s)
      Matsumoto Ayumi、Tsuda Hidetoshi、Furui Sadahiro、Kawada‐Nagashima Masako、Anzai Tatsuya、Seki Mitsuru、Watanabe Kazuhisa、Muramatsu Kazuhiro、Osaka Hitoshi、Iwamoto Sadahiko、Nishino Ichizo、Yamagata Takanori
    • Journal Title

      Molecular Genetics &amp; Genomic Medicine

      Volume: 10 Issue: 9

    • DOI

      10.1002/mgg3.2008

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Association of HLA-DPB1, NLRP10, OVOL1, and ABCC11 with the axillary microbiome in a Japanese population2022

    • Author(s)
      Kutsuwada Y., Yokota K., Yoshida K., Tsuda H., Watanabe K., Matsumoto A., Iwamoto S
    • Journal Title

      J Dertmatol Sci

      Volume: 105 Issue: 2 Pages: 98-104

    • DOI

      10.1016/j.jdermsci.2022.01.003

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ILDR2 stabilization is regulated by its interaction with GRP782021

    • Author(s)
      Watanabe Kazuhisa、Nakayama Kazuhiro、Ohta Satoshi、Matsumoto Ayumi、Tsuda Hidetoshi、Iwamoto Sadahiko
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 8414-8414

    • DOI

      10.1038/s41598-021-87884-7

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Two cases of DYNC1H1 mutations with intractable epilepsy2021

    • Author(s)
      Matsumoto Ayumi、Kojima Karin、Miya Fuyuki、Miyauchi Akihiko、Watanabe Kazuhisa、Iwamoto Sadahiko、Kawai Kensuke、Kato Mitsuhiro、Takahashi Yukitoshi、Yamagata Takanori
    • Journal Title

      Brain and Development

      Volume: 43 Issue: 8 Pages: 857-862

    • DOI

      10.1016/j.braindev.2021.05.005

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] N4BBP2L1 interacts with dynactin and contributes to GLUT4 trafficking and glucose uptake in adipocytes2021

    • Author(s)
      Watanabe K., Matsumoto A., Tsuda H., Iwamoto S
    • Journal Title

      J Diabetes Investig

      Volume: 12 Issue: 11 Pages: 1958-1966

    • DOI

      10.1111/jdi.13623

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genome‐Wide Association Study of Lean Nonalcoholic Fatty Liver Disease Suggests Human Leukocyte Antigen as a Novel Candidate Locus2020

    • Author(s)
      Yoshida Ken、Yokota Kazuha、Kutsuwada Yukinobu、Nakayama Kazuhiro、Watanabe Kazuhisa、Matsumoto Ayumi、Miyashita Hiroshi、Khor Seik‐soon、Tokunaga Katsushi、Kawai Yosuke、Nagasaki Masao、Iwamoto Sadahiko
    • Journal Title

      Hepatology Communications

      Volume: 4 Issue: 8 Pages: 1124-1135

    • DOI

      10.1002/hep4.1529

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 脂肪肝におけるリン脂質の変化とILDR2の役割2020

    • Author(s)
      渡邉和寿、中山一大、横田万葉、吉田健、松本歩、Leibel Rudolph、岩本禎彦
    • Organizer
      第74回日本栄養食糧学会大会
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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