Role of nuclear factor (erythroid-derived 2)-like 2 in metabolic homeostasis and insulin action: A novel opportunity for diabetes treatment?

Figure 1 Oxidative stress promotes anti-oxidative gene expression via nuclear factor (erythroid-derived 2)-like 2 activation. In a basal state, free Nrf2 level is very low because it forms a complex with Keap1 and the E3 ligase Cul3-Rbx-1, leading to its proteasome degradation. Under the stimulation of oxidative stress, the level of free Nrf2 increases as it is dissociated with Keap1. Free Nrf2 molecules will then enter the nuclei, bind to the cis-element ARE and stimulate the expression of Nrf2 target genes[7]. ARE: Antioxidant response element; Cul3: Cullin 3; E3: Ubiquitin ligase; Keap1: Kelch-like ECH-associated protein 1; Nrf2: Nuclear factor (erythroid-derived 2)-like 2; Rbx-1: RING box protein 1.

Figure 2 The potential pathways mediate the enhancement of the Nrf2 system on insulin signaling transduction. As a protective machinery, Nrf2 activation promotes the expression of a variety of key anti-oxidative enzymes that scavenge reactive oxidative species, attenuate oxidative stress-induced inflammatory activation, mitochondrial damage and ER stress. Subsequently, Nrf2 enhances insulin signaling by blocking the activation of IKKβ, PKC and JNK, respectively, that promotes the serine phosphorylation of IRS-1 and impairs the tyrosine phosphorylation of IRS-1 as well as subsequent insulin signaling transduction[28]. Furthermore, Nrf2 may directly enhance insulin signaling by an unidentified mechanism[15]. On the other hand, insulin signaling components, such as GSK-3 or mTOR, can promote Nrf2 function by regulating its content and nuclear location[49,50]. The Nrf2 activation, particularly the Nrf2-targeted gene products, heme oxygenase-1 and Mn-SOD, protects from oxidative stress-induced abnormalities and exerts a sensitizing action on insulin signaling[51,52]. ARE: Antioxidant response element; ER: Endoplasmic reticulum; GSK: Glycogen synthesis kinase; GST: Glutathione S-transferase; HO-1: Heme oxygenase-1; iNOS: Inducible nitric oxide synthase; IKK: Inhibitor of κB kinase; IRS: Insulin receptor substrate; JNK: C-Jun N-terminal kinase: mTOR: Mammalian target of rapamycin; Mn-SOD: Mn-superoxide dismutase; Nrf2: Nuclear factor (erythroid-derived 2)-like 2; PKB: Protein kinase B; PKC: Protein kinase C; TNFα: Tumor necrosis factor-α.