GW4064 attenuates lipopolysaccharide-induced hepatic inflammation and apoptosis through inhibition of the Toll-like receptor 4-mediated p38 mitogen-activated protein kinase signaling pathway in mice

Abstract

Liver injury is associated with devastating consequences caused by inflammation and apoptosis. The farnesoid X receptor (FXR) is a nuclear receptor that has an essential role in hepatoprotection by maintaining the homeostasis of liver metabolism. The present study investigated the capacity of the FXR agonist GW4064 to protect the livers of mice from lipopolysaccharide (LPS)-induced inflammation and apoptosis. Male C57BL/6J [wild-type (WT)] and FXR knockout (KO) mice were intraperitoneally injected with LPS or saline. LPS-treated mice were intraperitoneally injected with vehicle or GW4064 (20 mg/kg) twice and then sacrificed. Activation of FXR by GW4064 alleviated hepatic inflammation in the LPS-induced murine liver injury model as reflected by reduced serum levels of aspartate aminotransferase and pro-inflammatory cytokine mRNA expression, including tumor necrosis factor-α, as well as interleukin-6 and -1β i n W T m ice. I n addition, Toll-like receptor 4 (TLR4), p38 mitogen-activated protein kinase (MAPK), B-cell lymphoma-2-associated X protein and cytochrome c protein levels were decreased in WT mice receiving LPS with simultaneous GW4064 administration compared with those receiving LPS alone, while this was not observed in FXR KO mice. These results indicated that in WT mice, administration of GW4064 ameliorated LPS-mediated liver injury by upregulation of FXR expression, which was in part mediated by the TLR4/p38 MAPK pathway.