Nfe2l1, also known as Nrf1, is a highly conserved transcription factor belonging to the CNC-bZIP subfamily. It is essential for controlling redox balance, proteasome activity, and organ integrity. Nfe2l1 plays a crucial role in multiple pathways such as the ubiquitin-proteasome system, unfolded protein response, and antioxidative responses, which are vital for cellular stress adaptation [1]. Its dysregulation is associated with various diseases including neurodegenerative diseases, cancers, and metabolic disorders, making it an important target for research. Genetic models, especially KO/CKO mouse models, are valuable for studying its functions.

In adipocyte-specific Nfe2l1 knockout (Nfe2l1(f)-KO) mice, Nfe2l1 deficiency leads to an age-dependent whitening and shrinking of brown adipose tissue (BAT), along with down-regulation of proteasome, impaired mitochondrial function, reduced thermogenesis, pro-inflammation, and elevated regulatory cell death. Mechanistically, Nfe2l1 deficiency in brown adipocytes mainly results in down-regulation of lipolytic genes, decelerating lipolysis and causing BAT hypertrophy and cold intolerance. Single-nucleus RNA-sequencing reveals significant transcriptomic changes in BAT subpopulations, involving genes in lipid metabolism, proteasome, mitochondrial stress, etc. [3]. Also, Nfe2l1-deficient mice show brown adipose tissue involution, hyperubiquitination of ferroptosis regulators, and other hallmarks of ferroptosis, highlighting the role of Nfe2l1-proteasome pathway in ferroptosis [2].

In conclusion, Nfe2l1 is a key regulator in maintaining cellular homeostasis, with functions spanning redox balance, proteasome activity, and metabolism. Mouse models, especially Nfe2l1 KO/CKO models, have revealed its importance in processes like BAT thermogenesis, lipid metabolism, and protection from ferroptosis. These findings contribute to understanding diseases related to abnormal Nfe2l1 function, such as neurodegenerative diseases and metabolic disorders, potentially paving the way for novel therapeutic strategies.

References:

1. Liu, Xingzhu, Xu, Chang, Xiao, Wanglong, Yan, Nianlong. 2023. Unravelling the role of NFE2L1 in stress responses and related diseases. In Redox biology, 65, 102819. doi:10.1016/j.redox.2023.102819. https://pubmed.ncbi.nlm.nih.gov/37473701/

2. Kotschi, Stefan, Jung, Anna, Willemsen, Nienke, Conrad, Marcus, Bartelt, Alexander. 2022. NFE2L1-mediated proteasome function protects from ferroptosis. In Molecular metabolism, 57, 101436. doi:10.1016/j.molmet.2022.101436. https://pubmed.ncbi.nlm.nih.gov/34999280/

3. Shen, Wei, Ren, Suping, Hou, Yongyong, Zhang, Qiang, Pi, Jingbo. 2023. Single-nucleus RNA-sequencing reveals NRF1/NFE2L1 as a key factor determining the thermogenesis and cellular heterogeneity and dynamics of brown adipose tissues in mice. In Redox biology, 67, 102879. doi:10.1016/j.redox.2023.102879. https://pubmed.ncbi.nlm.nih.gov/37716088/