Inhibitory Effect Of RXR? Ligand K-80003 And Derivatives On Liver Fibrosis And Inflammation

Liver fibrosis resulted from chronic damage to the liver is characterized by the excessive accumulation of extracellular matrix proteins including collagen.Advanced liver fibrosis can lead to cirrhosis,liver failure,and liver cancer.The disease represents a common and difficult clinical challenge worldwide and the curative treatment for the disease is very limited.Nuclear receptors belong to a superfamily of transcription factors that regulate many metabolic pathways,including lipid and glucose metabolism,bile acid homeostasis,embryonic development,reproduction,inflammation,cell differentiation and tissue repair.It also affects liver regeneration,fibrosis and tumor formation.Nuclear receptor retinoid X receptor-alpha(RXRa)is a receptor for vitamin A metabolites and it is highly expressed in the liver.As the liver is the storage organ of retinoid and derivatives,altered expression and function of RXRa expression have been implicated in the process of hepatic fibrosis.Therefore,understanding the function of RXRa in liver fibrosis and its underlying molecular mechanism will be helpful to the development of therapeutic drugs for the disease.Recent data from our laboratory have found that RXRa ligand K-80003 can inhibit liver fibrosis via RXRa.On this basis,we screened the derivatives of K-80003 with the hope to identify more effective compounds for liver fibrosis.After screening,three new compounds,XS-0109,XS-0114 and XS-0243,with improved efficacy were obtained.Our data demonstrated that K-80003 and its derivatives could inhibit liver fibrosis and inflammation at both cellular and animal levels;and the anti-inflammation effect is in a RXRa dependent manner.While our data showed that K-80003 and its derivatives could not directly inhibit hepatic fibrosis through the Smad pathway,we showed that the anti-inflammatory effect of K-80003 and its derivatives was due to their modulation of the interaction between RXRa and the inflammatory protein TRAF2.Together,our results identify several potent anti-liver fibrosis compounds derived from K-80003 and reveal important molecular insight into their action.The new K-80003 derivatives represent promising compounds for future development.