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Release of ATP to the extracellular compartment and subsequent activation of purinergic receptors is a conserved mechanism mediating inflammatory responses and cell fate decisions in various organs including the liver. Previous findings suggest that extracellular ATP may promote liver tumorigenesis, however, the underlying mechanisms are poorly understood. Therefore, our aim was to dissect the functions of extracellular ATP and P2Y2 receptors (P2Y2R) during hepatocarcinogenesis. Liver tumors were induced in wild-type and P2y2r−/− knockout mice by intraperitoneal diethylnitrosamine (DEN) injection. Tumorigenesis was analyzed after 8 to 10 months and molecular analyses were performed at different stages of tumorigenesis in vivo, as well as in primary mouse hepatocytes in vitro. Liver tumor incidence and tumor numbers were strongly reduced in P2y2r−/− mice, whereas tumor size and morphology were comparable to wild-type controls, suggesting that P2Y2R contributes to tumor initiation. Mechanistically, hepatocyte proliferation in DEN-treated P2y2r−/− mice was reduced, which correlated with reduced c-JUN and CCND1 but increased p21 expression. Moreover, DNA damage as determined by hepatocellular expression of γH2A.X and of genes related to genotoxic stress, as well as STAT3 phosphorylation, was reduced in the absence of P2y2r. Administration of genotoxic agents to primary hepatocytes in vitro confirmed that DNA damage was indeed exacerbated by extracellular ATP, subsequent P2Y2R activation, and downstream intracellular calcium-dependent signal transduction. In conclusion, our data reveal that extracellular ATP and subsequent P2Y2R function stimulate DNA damage responses and hepatocyte proliferation, thereby promoting hepatocarcinogenesis. Targeting this pathway may be an attractive approach for chemoprevention of hepatocellular carcinoma.Significance:Extracellular ATP and subsequent P2Y2 receptor function stimulate DNA damage responses and hepatocyte proliferation, thereby promoting hepatocarcinogenesis in mice. Targeting this pathway may be an attractive approach for chemoprevention of hepatocellular carcinoma.

Background Zinc (Zn) and copper (Cu) are trace elements that serve as cofactors in catalytic processes with impact on immune responses. In patients with inflammatory bowel disease (IBD), decreased levels of serum Zn and Cu have been observed. Here, we investigated the effect of inflammation on serum concentrations of these trace elements in patients with IBD. Methods In this cross-sectional study, 98 patients with Crohn disease (CD) and 56 with ulcerative colitis (UC) were prospectively enrolled. Disease activity parameters, such as C-reactive protein (CRP) and fecal calprotectin (FC) were compared to serum Zn, Cu, and Cu/Zn ratio. Results Zinc insufficiency was observed in 11.2% of patients with CD and 14.3% with UC, Cu insufficiency in 20.4% with CD and 7.1% with UC. Anemia, hypoalbuminemia, increased FC, and elevated CRP were more frequently present in Zn-insufficient patients with IBD. In contrast, lower serum CRP values and a trend to lower FC were observed in Cu-insufficient patients. In multiple linear regression models adjusted for age, gender, and serum albumin, CRP positively correlated with serum Cu (P < 0.001) and the Cu/Zn ratio in both CD and UC (P < 0.001) but not with serum Zn concentrations. FC levels correlated only with the Cu/Zn ratio in patients with UC (P < 0.038). Conclusion Systemic inflammation inversely affected the serum Zn and Cu concentrations and, consequently, resulted in an increased Cu/Zn ratio., Lay Summary We found that zinc (Zn) and copper (Cu) insufficiency occurred in patients with inflammatory bowel disease and that systemic inflammation decreased serum Zn and increased Cu concentrations. This resulted in an increased Cu/Zn ratio. It may represent a novel parameter to assess disease activity.

Single-nucleotide polymorphisms in the gene encoding G protein-coupled receptor 35 (GPR35) are associated with increased risk of inflammatory bowel disease. However, the mechanisms by which GPR35 modulates intestinal immune homeostasis remain undefined. Here, integrating zebrafish and mouse experimental models, we demonstrate that intestinal Gpr35 expression is microbiota dependent and enhanced upon inflammation. Moreover, murine GPR35

Release of ATP to the extracellular compartment and subsequent activation of purinergic receptors is a conserved mechanism mediating inflammatory responses and cell fate decisions in various organs including the liver. Previous findings suggest that extracellular ATP may promote liver tumorigenesis, however, the underlying mechanisms are poorly understood. Therefore, our aim was to dissect the functions of extracellular ATP and P2Y

Increasing evidence has indicated that diet and metabolites, including bacteria- and host-derived metabolites, orchestrate host pathophysiology by regulating metabolism, immune system and inflammation. Indeed, autoimmune diseases such as inflammatory bowel disease (IBD) are associated with the modulation of host response to diets. One crucial mechanism by which the microbiota affects the host is signaling through G protein-coupled receptors (GPCRs) termed metabolite-sensing GPCRs. In the gut, both immune and nonimmune cells express GPCRs and their activation generally provide anti-inflammatory signals through regulation of both the immune system functions and the epithelial integrity. Members of GPCR family serve as a link between microbiota, immune system and intestinal epithelium by which all these components crucially participate to maintain the gut homeostasis. Conversely, impaired GPCR signaling is associated with IBD and other diseases, including hepatic steatosis, diabetes, cardiovascular disease, and asthma. In this review, we first outline the signaling, function, expression and the physiological role of several groups of metabolite-sensing GPCRs. We then discuss recent findings on their role in the regulation of the inflammation, their existing endogenous and synthetic ligands and innovative approaches to therapeutically target inflammatory bowel disease.