Journal
BIOMEDICINES
Volume 10, Issue 5, Pages -Publisher
MDPI
DOI: 10.3390/biomedicines10051032
Keywords
hepatic fibrosis; Hippo signalling pathway; hepatic stellate cells; empagliflozin
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Funding
- National Research Foundation of Korea (NRF) - Korea government (MSIT) [NRF-2020R1F1A1074019]
- Korea Initiative for fostering University of Research and Innovation Program of the NRF - Korean government (MSIT) [NRF2021M3H1A104892211]
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This study found that Empagliflozin improves liver fibrosis by activating the Hippo signaling pathway, reducing liver fibrosis in a mouse model, and reducing the expression of genes related to fibrosis.
Hepatic fibrosis is the excessive production and deposition of the extracellular matrix, resulting in the activation of the fibrogenic phenotype of hepatic stellate cells (HSCs). The Hippo/Yes-associated protein (YAP) signalling pathway is a highly conserved kinase cascade that is critical in regulating cell proliferation, differentiation, and survival, and controls stellate cell activation. Empagliflozin, a sodium-glucose cotransporter type-2 inhibitor, is an antidiabetic drug that may prevent fibrotic progression by reducing hepatic steatosis and inflammation. However, little is known about its mechanism of action in liver fibrosis. In this study, we used male C57 BL/6 J mice fed a choline-deficient, 1-amino acid-defined, high-fat diet (CDAHFD) as a model for hepatic fibrosis. For 5 weeks, the mice received either a vehicle or empagliflozin based on their assigned group. Empagliflozin attenuated CDAHFD-induced liver fibrosis. Thereafter, we identified the Hippo pathway, along with its effector, YAP, as a key pathway in the mouse liver. Hippo signalling is inactivated in the fibrotic liver, but empagliflozin treatment activated Hippo signalling and decreased YAP activity. In addition, empagliflozin downregulated the expression of pro-fibrogenic genes and activated Hippo signalling in HSCs. We identified a mechanism by which empagliflozin ameliorates liver fibrosis.
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