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Heme Oxygenase-1 Regulates Ferrous Iron and Foxo1 in Control of Hepatic Gluconeogenesis

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posted on 06.01.2021, 22:53 by Ada Admin, Wang Liao, Wanbao Yang, Zheng Shen, Weiqi Ai, Quan Pan, Yuxiang Sun, Shaodong Guo
The liver is a key player for maintaining glucose homeostasis. Excessive hepatic glucose production is considered to be a key for the onset of type 2 diabetes mellitus. The primary function of heme oxygenase-1 (HO1) is to catalyze the degradation of heme into biliverdin, ferrous iron, and carbon monoxide. Previous studies have demonstrated 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. Importantly, HO1 overexpression increased the generation of ferrous iron in the liver, which further activates NF-κB and phosphorylates Foxo1 at Ser273 to enhance gluconeogenesis. We further assessed the role of HO1 in insulin-resistant L-DKO (liver-specific knockout of IRS1 and IRS2 genes) mice, which exhibit upregulation 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 hepatic PKA→Foxo1 axis. Thus, our results demonstrate the role of HO1 in regulating hepatic iron status and Foxo1 to control gluconeogenesis and blood glucose.

Funding

This work was supported by National Institutes of Health grant (R01 DK095118 and R01 DK120968), American Diabetes Association Career Development Award (1-15-CD-09), Faculty Start-up funds from Texas A&M University Health Science Center and AgriLife Research, and USDA National Institute of Food and Agriculture grant (Hatch 1010958) to S.G (PI). Dr. S. G. is recipient of the 2015 American Diabetes Association Research Excellence Thomas R. Lee Award. This work was also partially supported by NIH R01DK118334 and R01AG064869 to YS (PI) and SG (Co-I).

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