Metabolic improvement and liver regeneration by inhibiting CXXC5 function for non-alcoholic steatohepatitis treatment

Abstract

Non-alcoholic liver disease: Treatment to stop suppression of crucial signaling pathway A small molecule treatment that restores the suppression of important signaling pathways could be effective against obesity-related liver disease. Non-alcoholic steatohepatitis (NASH) is a severe and prevalent condition in obese and diabetic patients. No specific NASH medications exist, but studies have shown that the Wnt/beta-catenin signaling pathway is crucial in activating key genes that fight the disease. Kang-Yell Choi at Yonsei University in Seoul, South Korea, and co-workers investigated the role of CXXC5, which suppresses the Wnt/beta-catenin pathway. They showed that mice with Cxxc5 knocked out were resistant to the worst effects of NASH. The researchers developed a treatment using a small molecule called KY19334 that interferes the function of CXXC5 via inhibition of its binding with Disheveled. This treatment suppressed inflammation, steatosis, oxidative stress and cell death, reversed liver fibrosis and enhanced liver regeneration. Non-alcoholic steatohepatitis (NASH) is a chronic liver disease that results from multiple metabolic disorders. Considering the complexity of the pathogenesis, the identification of a factor mediating the multiple pathogenic phenotypes of NASH will be important for treatment. In this study, we found that CXXC5, a negative feedback regulator of the Wnt/beta-catenin pathway, was overexpressed with suppression of Wnt/beta-catenin signaling and its target genes involved in hepatic metabolism in obese-NASH patients. Cxxc5(-/-) mice were found to be resistant to NASH pathogenesis with metabolic improvements. KY19334, a small molecule that activates the Wnt/beta-catenin pathway via interference of the CXXC5-Dvl interaction, reversed the overall pathogenic features of NASH as Cxxc5(-/-) mice. The improvement in NASH by KY19334 is attributed to its regenerative effects through restorative activation of the suppressed Wnt/beta-catenin signaling. Overall, the pronounced metabolic improvements with the stimulation of liver regeneration by interfering with the CXXC5-Dvl interaction provide a therapeutic approach for NASH.