Functional analysis of hepatic stellate cell-expressed FXR in liver cirrhosis and carcinogenesis

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K18012
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry; Biological pharmacy
• Research Institution: Osaka City University
• Principal Investigator: Tsutomu Matsubara 大阪市立大学, 大学院医学研究科, 准教授 (20628698)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: FXR / 肝星細胞 / 加齢 / 肝硬変 / 線維化

Outline of Final Research Achievements

Bile acid receptor (Farnesoid X receptor: FXR) is an important factor for maintaining the homeostasis of bile acid, and is known to suppressively act on liver cirrhosis and liver cancer. However, FXR, which is highly expressed in hepatic stellate cells, has been suggested to have an inhibitory effect on the cultured cells, but its evaluation in vivo was poor. In the present study, mice with knockout of the FXR gene in hepatic stellate cells were observed to have increased aging-induced liver fibrosis, as in mice with a systemically deficient FXR gene. Moreover, since FXR regulates senescence-related genes in the primary human hepatic stellate cell line HHSteC, this study indicated a possibility that molecular association exists in senescence, liver fibrosis and FXR.

Free Research Field

肝臓病学

Academic Significance and Societal Importance of the Research Achievements

肝硬変や肝がんは、背景肝疾患に関係なく、慢性肝炎の終末像であり、効果的な治療薬は存在しない。また、高齢者ほど肝硬変や肝がんが発症するリスクが高くなることが知られている。今後、加齢に伴う肝線維化亢進の分子メカニズム、細胞が老化していく過程におけるFXRの役割など、詳細な研究が必要とされるが、本研究成果は、肝星細胞のFXRを標的とする治療戦略が可能であることを示唆している。