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

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/β-catenin pathway, was overexpressed with suppression of Wnt/β-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/β-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/β-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.

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Seol Hwa Seo, Eunhwan Kim, Minguen Yoon, Soung-Hoon Lee, Byung-Hyun Park, Kang-Yell Choi

期刊 Exp Mol Med
影响因子 12.9
起止号 2022 Sep;54(9):1511-1523.
种属 Mouse
技术平台抗体芯片
应用领域消化系统
研究方向消化系统
疾病类型肝炎
检测蛋白 Adiponectin/Acrp30,DPPIV/CD26,IL-27,Amphiregulin,EGF,IL-28,Angiopoietin-1,Endoglin/CD105,IL-33,Angiopoietin-2,Endostatin,LDL R,Angiopoietin-like 3,Fetuin A/AHSG,Leptin,BAFF/BLyS/TNFSF13B,FGF acidic,LIF,C1q R1/CD93,FGF-21,Lipocalin-2/NGAL,CCL2/JE/MCP-1,Flt-3 Ligand,LIX,CCL3/CCL4 MIP-1 alpha/beta,Gas6,M-CSF,CCL5/RANTES,G-CSF,MMP-2,CCL6/C10,GDF-15,MMP-3,CCL11/Eotaxin,GM-CSF,MMP-9,CCL12/MCP-5,HGF,Myeloperoxidase,CCL17/TARC,ICAM-1/CD54,Osteopontin (OPN),CCL19/MIP-3 beta,IFN-gamma,Osteoprotegerin/TNFRSF11B,CCL20/MIP-3 alpha,IGFBP-1,PD-ECGF/Thymidine phosphorylase,CCL21/6Ckine,IGFBP-2,PDGF-BB,CCL22/MDC,IGFBP-3,Pentraxin 2/SAP,CD14,IGFBP-5,Pentraxin 3/ TSG-14,CD40/TNFRSF5,IGFBP-6,Periostin/OSF-2,CD160,IL-1 alpha/IL1F1,Pref-1/DLK-1/FA1,Chemerin,IL-1 beta/IL-1F2,Proliferin,Chitinase 3-like 1,IL-1ra/IL-1F3,Proprotein Convertase 9/PCSK9,Coagulation Factor III/Tissue Factor,IL-2,RAGE,Complement Component C5/C5a,IL-3,RBP4,Complement Factor D,IL-4,Reg3G,C-Reactive Protein/CRP,IL-5,Resistin,CX3CL1/Fractalkine,IL-6,E-Selectin/CD62E,CXCL1/KC,IL-7,P-Selectin/CD62P,CXCL2/MIP-2,IL-10,Serpin E1/PAI-1,CXCL9/MIG,IL-11,Serpin F1/PEDF,CXCL10/IP-10,IL-12p40,Thrombopoietin,CXCL11/I-TAC,IL-13,TIM-1/KIM-1/HAVCR,CXCL13/BLC/BCA-1,IL-15,TNF-alpha,CXCL16,IL-17A,VCAM-1/CD106,Cystatin C,IL-22,VEGF,Dkk-1,IL-23,WISP-1/CCN4
doi doi: 10.1038/s12276-022-00851-8.

Abstract

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/β-catenin pathway, was overexpressed with suppression of Wnt/β-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/β-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/β-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.

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