Investigation of Novel Renal Lipid Metabolic Drug Targeting Carboxylesterase 1

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K22921
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0903:Organ-based internal medicine and related fields
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Sugahara Sho 滋賀医科大学, 医学部, 客員助教 (80880682)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Keywords: 近位尿細管 / 脂質代謝 / Carboxylesterase 1

Outline of Final Research Achievements

We focused on the lipid-metabolizing activity of Carboxilesterase 1 (CES1) in the kidney to investigate its potential as a therapeutic target for chronic kidney disease (CKD). We found that CES1 expression in the kidney is upregulated in a high-fat diet(HFD) mouse model. We also found that maintenance of FXR activity, one of the transcription factors of CES1, reduced tubular damage during HFD feeding.
We overexpressed CES1 in human renal proximal tubular cell lines and co-cultured it with palmitic acid and oleic acid, and observed the cytotoxic effect of fatty acid loading. However, no improvement in cytotoxicity was observed in CES1-overexpressing cells upon fatty acid loading.

Free Research Field

腎臓内科

Academic Significance and Societal Importance of the Research Achievements

腎臓の近位尿細管においてCES1がFXRの調節を受け、脂肪負荷時における脂質代謝能の維持に寄与していることが明らかとなり、これらを標的とした薬剤が脂質代謝異常に伴う腎障害の改善薬となりうる可能性を示した。
培養尿細管においてCES1過剰発現時の代謝障害改善作用は未だ示されていないが、これには培養細胞における代謝変化（近位尿細管は主として脂質をエネルギー源とするが、培養細胞の場合、エネルギー需要が糖質に傾いていることがある）が起因する可能性が考えられた。これに関しても今後、近位尿細管の脱分化、線維化に伴う代謝変化にも着目して検討を続けていく予定である。