FoxO6-mediated TXNIP induces hepatic steatosis through NLRP3 inflammasome activation in vivo and in vitro

Background We showed that the activation of the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) inflammasome by the forkhead box O6 (FoxO6) transcription factor through binding of the thioredoxin-interacting protein (TXNIP) under inflammatory conditions might lead to hepatic steatosis. Although the role of the FoxO6 in mediating lipid accumulation and the chronic inflammatory process underlying the pathophysiology of hepatic steatosis are well explored, the precise mechanisms of the involvement of FoxO6 have not fully been delineated to date. Methods NLRP3 inflammasome and lipogenesis were monitored in mice overexpressed with constitutively active (CA)-FoxO6 allele, and FoxO6-null mice. In vitro study, liver cells overexpressing CA-FoxO6 were treated with palmitate, and then alterations in lipid metabolism were measured. Results The focus of our investigation was to apply palmitate treatment to elucidate the mechanisms underlying the role of FoxO6 in the activation of the cytokine IL-1β through the NLRP3 inflammasome. Initial experiments revealed that palmitate-induced FoxO6 activity was caused by its dephosphorylation, which induced its transcriptional activity. Further palmitate experiments showed increased expression of IL-1β and the hepatic NLRP3 inflammasome complex, including adapter protein ASC, and pro-caspase-1. Furthermore, TXNIP, a key regulator of cellular redox state in the upstream NLRP3 inflammasome, was induced by FoxO6 in liver and HepG2 cells. Conclusion The main contribution of the current study is the identification of FoxO6 as a key signaling element upstream of TXNIP in the regulation of the hepatic NLRP3 inflammasome of the molecular mechanisms involved in hepatic lipogenesis.