抄録
Nuclear factor erythroid 2-related factor 1 (NFE2L1, also known as NRF1), an ubiquitously expressed CNC-bZIP protein, is an important regulator of antioxidant response, proteasome homeostasis, genetic stability, mitochondrial respiration, inflammation, lipid metabolism and cell differentiation. With regard to the relevance of NRF1 to toxicology, emerging evidence reveals that toxic metals, such as arsenic, may activate NRF1-mediated adaptive antioxidant response. In addition, silencing of Nfe2l1 may affect various types of cells to the toxicity of oxidative stressors and other toxicants. Recently, we found that silencing of Nfe2l1 in mouse pancreatic β-cells, led to a phenotype markedly resembling pre-T2D conditions with disrupted glucose metabolism and impaired insulin secretion. The impaired glucose responsiveness due to Nfe2l1 silencing is likely a result of aberrant expression of a group of glucose metabolic enzymes. The findings demonstrated an important role of NRF1 in regulating glucose metabolism and insulin secretion in pancreatic β-cells and characterized NRF1 as a key transcription factor that regulates the coupling between glycolysis and mitochondrial metabolism as well as insulin secretion. On the other hand, mature adipocyte-specific knockout mice (Nfe2l1(f)-KO) developed age-dependent leanness and abnormal fat distribution. Notably, adult Nfe2l1(f)-KO mice exhibited a dramatically reduced mass of subcutaneous adipose tissue (SAT). Histomorphometric analysis of SAT and visceral adipose tissue invariably showed adipocyte hypertrophy and severe adipose inflammation in Nfe2l1(f)-KO mice. Moreover, Nfe2l1(f)-KO mice exhibited a metabolic syndrome with reduced ectopic lipid accumulation. Mechanistic studies revealed that Nfe2l1 deficiency disturbed the dynamic of lipolysis in adipocytes, leading to adipocyte hypertrophy followed by inflammation, pyroptosis, and insulin resistance. The findings established a novel role of NRF1 in regulating adipose tissue plasticity and metabolic profile, the disruption of which can lead to altered fat distribution and impaired glucose and lipid homeostasis. Taken together, our studies highlight the important regulatory roles of NRF1 in metabolic homeostasis of glucose and lipid. Clearly, the relevance and importance of NRF1 in mechanistic toxicology and risk assessment of toxicants, in particular oxidative stressors, need further investigation.
