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

Abstract

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. 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 nuclear factor-κB and phosphorylates Foxo1 at Ser273 to enhance gluconeogenesis. We further assessed the role of HO1 in insulin-resistant liver-specific knockout of IRS1 and IRS2 genes (L-DKO) 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 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.

Enhanced sciatic nerve regeneration by relieving iron-overloading and organelle stress with the nanofibrous P(MMD-co-LA)/DFO conduits

“…HO-1 catalyzes the decomposition of heme into biliverdin, carbon monoxide and ferrous iron. Overexpression of HO-1 produces excess ferrous iron [ 53 , 54 ]. In PDPLA group, HO-1 was overexpressed (about twice that of the control group), while the expression of HO-1 recovered in PDPLA/DFO group ( Fig.…”

Anti-Diabetic Indole-Terpenoids From Penicillium sp. HFF16 Isolated From the Rhizosphere Soil of Cynanchum bungei Decne

“…Compounds 1–5 were nontoxic against HepG2 cells by MTT assay at the concentration of 100 μM ( Figure 5A ). Excessive hepatic glucose production was considered to be a key for the onset of diabetes ( Liao et al, 2021 ). The hepatic glucose production in response to all the compounds was evaluated, and EC50 values were used to assess their potencies.…”

Humulane-Type Macrocyclic Sesquiterpenoids From the Endophytic Fungus Penicillium sp. of Carica papaya

“…The liver plays a major role in whole body glucose metabolism by maintaining a balance between glucose production and glucose storage. Excessive hepatic glucose production contributes substantially to diabetes, and it is proposed that suppression of hepatic glucose production may provide therapeutic advantages for the control of diabetes ( Xiao et al, 2017 ; Liao et al, 2021 ). To investigate the anti-diabetic effect of the six compounds, we examined the glucose production in hepatocytes.…”