Activation of Pregnane X Receptor Prevents Lipopolysaccharide/D‐Galactosamine‐induced Acute Liver Failure in Mice

Abstract

Pregnane X receptor (PXR) plays crucial roles in xenobiotic and endobiotic metabolism. Recent work has shown that PXR participate in anti‐apoptotic and anti‐inflammatory processes. However, its in vivo function in the pathogenesis of inflammation‐related apoptotic liver injury remains obscure. The role of PXR in liver injury was investigated using lipopolysaccharide (LPS)/D‐galactosamine (GalN)‐induced and TNFα‐dependent acute liver failure mouse model. Our findings demonstrated that PXR‐null mouse liver had a delayed initial response to LPS/GalN characterized by a late activation of Stat3 and NF¿B and reduced TNFα production in comparison with wild‐type mouse liver. However, PXR‐null mouse later developed a vigorous response including strong and sustained activation of Stat3 and JNK1/2, increased production of hepatic pro‐inflammatory cytokines and chemokines, as well as enhanced liver apoptosis and necrosis and increased susceptibility to LPS/GalN‐induced lethality. In addition, activating PXR protected mice from LPS/GalN‐induced acute liver injury and death. The underlying protective mechanisms include inhibition of TNFα, IL‐1β, and IL‐6 production, repression of sustained JNK1/2 activation, increased expression of anti‐apoptotic protein (Bcl‐xL), and blockage of expression of pro‐apoptotic proteins (cleaved caspase‐3 and Bax). Our data indicate that PXR ligands may be useful clinically to prevent TNFα‐dependent liver injury during acute inflammation.