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, l-
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.