Activation of LGR4 by Rspol significantly reduced tumor necrosis factor-alpha (TNFalpha)-induced cell death, and levels of NF-KB-p65 and caspase-3 in cultured hepatocytes. Knockdown of hepatic LGR4 rendered hepatocytes more vulnerable to TNFa-induced damage in cultured primary cells and in the setting of HIRI and LPS/D-Gal-induced liver injury. Rspol potentiated both basal and Wnt3alpha-induced stabilization of p-catenin. Disruption of beta-catenin signaling reversed the protective effects of Rspol on TNFalpha-induced hepatocyte toxicity. LGR4 knockdown increased nuclear transiocation of NF-KappaB-p65 in response to acute injury. Overexpression of IKKbeta attenuated the protective effects of Rspol on TNFalpha-induced cell death. In conclusion, the Rspol-LGR4 system represents a novel pathway for cyto-protection and modulation of stress-induced tissue damage.
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