Pharmacological study of intracellular signaling pathways involved in hepatic stellate cell reversion for treatment of NASH

2018 Fiscal Year Final Research Report

• Project/Area Number: 17H07000
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Applied health science
• Research Institution: University of Shizuoka
• Principal Investigator: Yamaguchi Momoka 静岡県立大学, 薬学部, 助教 (30804819)
• Research Collaborator: Morishita Tomoya
• Project Period (FY): 2017-08-25 – 2019-03-31
• Keywords: 肝星細胞 / 肝線維化 / 脱活性化 / 形質転換

Outline of Final Research Achievements

During liver injury, quiescent hepatic stellate cells (qHSCs) are transdifferentiated into myofibroblast-like activated HSCs (aHSCs), which produce collagen, a major source of liver fibrosis. Therefore, the reversion of aHSC is regarded as a therapeutic target for liver fibrosis. In this study, caffeine (0.1-10 mM) significantly decreased the expression of α-SMA and COL1a1, are markers of aHSC, in a concentration-dependent manner. Further, caffeine significantly increased of the expression of MMP-9 which is a marker of qHSC. CGS-15943, a subtype-nonselective adenosine receptor inhibitor, significantly decreased the expression α-SMA, but had no significant effect on the expression of COL1a1 and MMP-9. These results suggest that caffeine causes the reversion of aHSC and a part of the mechanism of the aHSC reversion is mediated by inhibiting adenosine receptors. We propose that these results lead to effective therapeutic strategies for preventing liver fibrosis.

Free Research Field

肝臓の線維化

Academic Significance and Societal Importance of the Research Achievements

肝線維化の責任細胞ということから肝星細胞に関する報告は数多くあるものの、本研究で示したような一度活性化した活性型HSCを静止型HSCに脱活性化させるという報告は少なく、その機構は殆ど分かっていない。すなわち、本研究で示したHSC脱活性化機構の解明は、学術的新規性が高い。さらに、そのシグナル伝達の解明は未だ有効な治療方法が存在しないNASH治療薬の開発に繋がることが期待でき、臨床的な意義も大きい。