Interleukin-22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury

Interleukin 22 (IL-22) is an epithelial survival cytokine that is at present being explored as therapeutic agents for acute and chronic liver injury. However, its molecular basis of protective activities remains poorly understood. Here we demonstrate that IL-22 inhibits the deteriorating metabolic states induced by stimuli in hepatocytes. Specifically, we provide evidence that IL-22 promotes oxidative phosphorylation (OXPHOS) and glycolysis and regulates the metabolic reprogramming related transcriptional responses. IL-22 controls metabolic regulators and enzymes activity through the induction of AMP-activated protein kinase (AMPK), AKT and mammalian target of rapamycin (mTOR), thereby ameliorating mitochondrial. The upstream effector lncRNA H19 also participates in the controlling of these metabolic processes in hepatocytes. Importantly, amelioration of liver injury by IL-22 through activation of metabolism relevant signaling and regulation of mitochondrial function are further demonstrated in cisplatin-induced liver injury and steatohepatitis. Collectively, our results reveal a novel mechanism underscoring the regulation of metabolic profiles of hepatocytes by IL-22 during liver injury, which might provide useful insights from the bench to the clinic in treating and preventing liver diseases. Graphical AbstractOur works demonstrate a critical role of IL-22 in regulating hepatocellular metabolism to treat liver injury via activating STAT3-lncRNA H19-AMPK-AKT-mTOR axis. These findings describe a novel mechanism underscoring the regulation of metabolic states of hepatocytes by IL-22 during liver injury with potentially broad therapeutic insights. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/892927v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@c6308corg.highwire.dtl.DTLVardef@19d6e17org.highwire.dtl.DTLVardef@a6e661org.highwire.dtl.DTLVardef@15f129e_HPS_FORMAT_FIGEXP M_FIG C_FIG