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Regulatory mechanism of ABCA1 expression involved in lipotoxicity in pancreatic beta cells.

Research Project

Project/Area Number 19K23970
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0902:General internal medicine and related fields
Research InstitutionKagawa University

Principal Investigator

Sato Seisuke  香川大学, 医学部附属病院, 助教 (50843504)

Project Period (FY) 2019-08-30 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsABCA1 / 脂肪毒性 / 膵β細胞 / 2ME / インスリン分泌 / ペマフィブラート / インスリン / GLP-1 / 糖尿病 / TNF-α
Outline of Research at the Start

我々はHDL代謝のメイン分子であるABCA1が膵β細胞の脂肪毒性に関わることを報告してきた。TNF-αはp38-MAPKを介してABCA1の発現を低下させ、脂肪毒性を惹起し、インスリン分泌も低下させることを明らかにした。しかし、ABCA1遺伝子は複数の細胞内情報伝達系により制御されており、発現に寄与する因子は多岐に渡るため、その詳細は不明である。そこで今回は膵β細胞のABCA1を起点にリバースプロテオミクスの手法で、脂肪毒性を誘導する細胞内情報伝達系を網羅的に解析する研究計画である。

Outline of Final Research Achievements

Since 2-Methoxyestradiol (2ME), a major metabolite of estradiol, is thought to be involved in lipotoxicity, we first investigated whether 2ME affects ABCA1 expression in HepG2 cells, a cultured hepatocyte cell line. We found that 2ME increased ABCA1 expression in HepG2 cells and decreased lipid droplets in HepG2 cells. 2ME-induced ABCA1 expression was suppressed by PI3K inhibitor and induced by increased expression of Akt and p110 downstream of PI3K, indicating the involvement of the PI3/Ak pathway. We also found that the PI3/Ak pathway is involved.

Academic Significance and Societal Importance of the Research Achievements

国民病である糖尿病は脂肪毒性と密接に関与している。このため糖尿病をコントロールするためには脂肪毒性の特徴を把握することが重要である。細胞内の脂肪量を調節する分子としてABCA1は非常に重要なものであり、ABCA1の発現を増強すると脂肪毒性が解消され糖尿病もよくなる可能性が高い。今回女性ホルモンの代謝物である2MEがABCA1の発現を増強することを発見した。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (4 results)

All 2022 2021 2020

All Journal Article (4 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 4 results,  Open Access: 4 results)

  • [Journal Article] Effects of 2-Methoxyestradiol, a Main Metabolite of Estradiol on Hepatic ABCA1 Expression in HepG2 Cells2022

    • Author(s)
      Ibata T, Lyu J, Imachi H, Fukunaga K, Sato S, Kobayashi T, Saheki T, Yoshimura T, Murao K.
    • Journal Title

      Nutrients.

      Volume: Jan 11;14(2) Issue: 2 Pages: 288-288

    • DOI

      10.3390/nu14020288

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] AGEs inhibit scavenger receptor class B type I gene expression via Smad1 in HUVECs2021

    • Author(s)
      Nagata Hiromi、Lyu Jingya、Imachi Hitomi、Fukunaga Kensaku、Sato Seisuke、Kobayashi Toshihiro、Saheki Takanobu、Seo Kayoko、Salimah Japar B、Iwama Hisakazu、Sakamoto Ryuichi、Ogawa Yoshihiro、Murao Koji
    • Journal Title

      Journal of Molecular Endocrinology

      Volume: 66 Issue: 3 Pages: 223-231

    • DOI

      10.1530/jme-20-0177

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Oxidized LDL Downregulates ABCA1 Expression via MEK/ERK/LXR Pathway in INS-1 Cells2021

    • Author(s)
      Lyu J, Fukunaga K, Imachi H, Sato S, Kobayashi T, Saheki T, Ibata T, Yoshimura T, Iwama H, Murao K.
    • Journal Title

      Nutrients.

      Volume: Aug 29;13(9) Issue: 9 Pages: 3017-3017

    • DOI

      10.3390/nu13093017

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Role of ATP-binding cassette transporter A1 in suppressing lipid accumulation by glucagon-like peptide-1 agonist in hepatocytes2020

    • Author(s)
      Lyu J, Imachi H, Fukunaga K, Sato S, Kobayashi T, Dong T, Saheki T, Matsumoto M, Iwama H, Zhang H, Murao K
    • Journal Title

      Mol Metab

      Volume: 34 Pages: 16-26

    • DOI

      10.1016/j.molmet.2019.12.015

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research

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Published: 2019-09-03   Modified: 2023-01-30  

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