Heme oxygenase-1 regulates ferrous iron and foxo1 in control of hepatic gluconeogenesis

Abstract

The liver is a key player for maintaining glucose homeo-stasis. Excessive hepatic glucose production is consid-ered to be a key for the onset of type 2 diabetes. The primary function of heme oxygenase-1 (HO1) is to cat-alyze the degradation of heme into biliverdin, ferrous iron, and carbon monoxide. Previous studies have dem-onstrated that the degradation of heme by HO1 in the liver results in mitochondrial dysfunction and drives insulin resistance. In this study, by overexpressing HO1 in hepatocytes and mice, we showed that HO1 promotes gluconeogenesis in a Foxo1-dependent manner. Impor-tantly, HO1 overexpression increased the generation of ferrous iron in the liver, which further activates nuclear factor-kB and phosphorylates Foxo1 at Ser273 to en-hance gluconeogenesis. We further assessed the role of HO1 in insulin-resistant liver-specific knockout of IRS1 and IRS2 genes (L-DKO) mice, which exhibit upregula-tion of HO1 in the liver and hepatic ferrous iron overload. HO1 knockdown by shRNA or treatment of iron chelator rescued the aberrant gluconeogenesis in L-DKO mice. In addition, we found that systemic iron overload promotes gluconeogenesis by activating the hepatic protein kinase A→Foxo1 axis. Thus, our results demonstrate the role of HO1 in regulating hepatic iron status and Foxo1 to control gluconeogenesis and blood glucose.