| Nrf1 and Nrf2 are CNC-bZIP proteins that bind to the Antioxidant Response Element (ARE) and mediate expression of several phase II metabolic enzymes. Despite significant structural homology between these two transcription factors, they exhibit different functions. Nrf2, although dispensable for development, is crucial for regulation of basal and induced antioxidant gene expression. In contrast, Nrf1 appears to play a minor role in mediation of the oxidative stress response but is essential for embryogenesis and normal hepatocyte function.;Our studies here delve further into the specific functions of Nrf1 and Nrf2. We first investigate whether Nrf1 and Nrf2 exhibit functional redundancy by analyzing mice that are deficient in both Nrf1 and Nrf2. These double knockout animals die during early gestation and exhibit extensive apoptosis that is inherent to the loss of Nrf1 and Nrf2 function. Apoptosis is attributable to exacerbation of decreased antioxidant gene expression already present in single knockout cells. Analysis of Nrf1 and Nrf2 function beyond mediation of antioxidant gene expression reveals distinct roles for both transcription factors. Nrf1 appears to be involved in ER homeostasis as loss of Nrf1 in mouse liver leads to activation of the PERK pathway in the unfolded protein response (UPR). Nrf1 knockout fibroblasts similarly show increased susceptibility to ER stressors, suggesting that the effect in liver is primary. Dysregulation of ER homeostasis in Nrf1LKO livers culminate in apoptosis mediated by CHOP, caspase 9, and caspase 3. Our investigations also reveal a novel function for Nrf2 as a regulator of adipogenesis. Nrf2 knockout mice are resistant to high fat diet-induced obesity. This defect appears to be intrinsic to adipocytes, as cells deficient in Nrf2 function exhibit decreased adipogenesis due to down-regulation of key regulators involved in adipocyte differentiation.;Altogether, we demonstrate that Nrf1 and Nrf2 not only have a collective function in mediating antioxidant response, but also individual roles in regulating ER homeostasis and adipogenesis, respectively. |
