1718-P: Heme Oxygenase-1 Promotes Hepatic Glucose Production via Increasing the Intracellular Ferrous Iron

The heme oxygenase-1 (HO1) catalyzes the degradation of heme into biliverdin, ferrous iron and carbon monoxide (CO). Although HO1 has long been considered as an anti-inflammatory molecule, recent studies showed that HO1 disrupts the mitochondrial function in hepatocytes, as well as drives inflammation and insulin resistance in mice and humans. Such different findings from the historical view impelled us to further investigate the roles of HO1 in glucose metabolism. In the present study, we found that overexpression of HO1 promoted hepatic glucose production (HGP) in hepatocytes from the wild type (WT) mice, which was comparable to the treatment of glucagon. Since the regulatory roles of the transcription factor forkhead box O1 (Foxo1) in HGP have been well recognized, we then generated the liver-specific Foxo1 knockout (L-FKO) mice to study the contribution of Foxo1 in mediating the effects of HO1. We found that HO1 overexpression did not have a significant effect in promoting HGP in hepatocytes from the L-FKO mice, suggesting HO1 improved HGP dependent on Foxo1. Besides, HO1 overexpression improved the mRNA levels of Foxo1-targeted gluconeogenic genes and increased the phosphorylation of Foxo1 at Ser273, which is a phosphorylation site integrating into the glucagon signaling. We also found that HO1 overexpression activated p38α and p65/NF-κB in hepatocytes. Further study using siRNA or specific inhibitor demonstrated that p65/NF-κB, but not p38α, mediated the HO1-induced pFoxo1-S273 and HGP in hepatocytes. We then explored the role of HO1-induced ferrous iron in activating p65/NF-κB and promoting HGP. We found that HO1 overexpression in hepatocytes substantially increased the intracellular ferrous iron. The pretreatment of iron chelator deferoxamine mesylate diminished the effects of HO1 overexpression on p65/NF-κB, pFoxo1-S273, and HGP. Taken together, results from this study revealed the mechanisms of HO1 in driving HGP, which is through the generation of ferrous iron.