Research Article: LY2405319, an analog of fibroblast growth factor 21 ameliorates α-smooth muscle actin production through inhibition of the succinate—G-protein couple receptor 91 (GPR91) pathway in mice

Date Published: February 14, 2018

Publisher: Public Library of Science

Author(s): Cong Thuc Le, Giang Nguyen, So Young Park, Dae Hee Choi, Eun-Hee Cho, Partha Mukhopadhyay.


Fibroblast growth factor 21 (FGF21) is an important metabolic regulator expressed predominantly in the liver. In this study, we evaluated the role of LY2405319, an analogue of FGF21, in hepatic stellate cell (HSC) activation and in a methionine and choline-deficient (MCD)-diet induced mouse model of liver fibrosis. During liver injury, HSCs trans-differentiate into activated myofibroblasts which produce alpha-smooth muscle actin (α-SMA) and become a major cell type in hepatic fibrogenesis. Succinate and succinate receptor (GPR91) signaling has emerged as a regulator to promote α-SMA production in MCD diet- induced mice. Treatment with palmitate or MCD medium on LX-2 cells (HSCs) increased succinate concentration in the conditioned medium and cell lysate of LX-2 cells and increased production of GPR91 and α-SMA. However, LY2405319 administration ameliorates palmitate or MCD media-induced succinate production and decreases over-expression of GPR91 and α-SMA in LX2-cells. In an in vivo study, the MCD diet treatment caused increased steatohepatitis and liver fibrosis compared with the control diet in mice. Administration of LY2405319 improved steatohepatitis ameliorated GPR91 and α -SMA production in the liver, decreased succinate concentration in both liver and serum of MCD diet -induced mice. These results suggest that FGF21 reduces production of α-SMA by inhibiting the succinate-GPR91 pathway. We conclude that FGF21 acts as an inhibitor of the succinate-GPR91 pathway to control liver fibrosis. This suggests that FGF21 has therapeutic potential for treating liver fibrogenesis.

Partial Text

Hepatic fibrosis is a wound- healing response to chronic liver injury. During liver injury, activation of hepatic stellate cells (HSCs) is a major process to produce extracellular matrix structures, which eventually leads to the development of liver fibrosis [1,2].

In this study, we tested whether LY2405319, an FGF21 analogue, can be a potential therapeutic treatment for hepatic fibrosis by inhibiting HSC activation via suppressing succinate-GPR91 signaling in an MCD diet -induced mouse model of liver fibrosis. LY2405319 used as the modification of FGF21, show the same in efficacy and biological activity with native human FGF21 in cell-based, rodent, and non- human primate assay[16,17].




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