The roles of NFE2L1 in adipocytes: Structural and mechanistic insight from cell and mouse models

Abstract

Adipocytes play pivotal roles in maintaining energy homeostasis by storing lipids in adipose tissue (AT), regulating the flux of lipids between AT and the circulation in response to the body's energy requirements and secreting a variety of hormones, cytokines and other factors. Proper AT development and function ensure overall metabolic health. Nuclear factor erythroid 2-related factor 1 (NFE2L1, also known as NRF1) belongs to the CNC-bZIP family and plays critical roles in regulating a wide range of essential cellular functions and varies stress responses in many cells and tissues. Human and rodent Nfe2l1 genes can be transcribed into multiple splice variants resulting in various protein isoforms, which may be further modified by a variety of post-translational mechanisms. While the long isoforms of NFE2L1 have been established as master regulators of cellular adaptive antioxidant response and proteasome homeostasis, the exact tissue distribution and physiological function of NFE2L1 isoforms, the short isoforms in particular, are still under intense investigation. With regard to key roles of NFE2L1 in adipocytes, emerging data indicates that deficiency of Nfe2l1 results in aberrant adipogenesis and impaired AT functioning. Intriguingly, a single nucleotide polymorphism (SNP) of the human NFE2L1 gene is associated with obesity. In this review, we summarize the most significant findings regarding the specific roles of the multiple isoforms of NFE2L1 in AT formation and function. We highlight that NFE2L1 plays a fundamental regulatory role in the expression of multiple genes that are crucial to AT metabolism and function and thus could be an important target to improve disease states involving aberrant adipose plasticity and lipid homeostasis.

Nrf1 is an indispensable redox-determining factor for mitochondrial homeostasis by integrating multi-hierarchical regulatory networks

“…Those antioxidant genes mediated by Nrf1 and/or Nrf2 are mainly involved in: i) glutathione production and regeneration, which are regulated by glutamate-cysteine ligase modifier (GCLM) and catalytic subunits (GCLC), glutathione reductase (GSR) [ 13 ]; ii) glutathione utilization, which is conducted by glutathione S-transferases (GSTs) and glutathione peroxidase 2 (GPXs); iii) thioredoxin production and utilization (e.g., TXNs, PRDXs); iv) NADPH production, controlled by glucose-6-phosphate dehydrogenase (G6PD), malic enzyme 1 (ME1) and isocitrate dehydrogenase 1 (IDH1) [ 14 ]; and v) the other responsible genes for antioxidant and detoxification, e.g., both encoding NAD(P)H:quinone oxidoreductase 1 (NQO1) [ 15 ] and heme oxygenase 1 (HO1) [ 16 ]. Furthermore, Nrf1 acts as a vital player in maintaining protein homeostasis (proteostasis), lipid metabolism, glucose metabolism, inflammation, cell differentiation, and embryonic development by controlling transcriptional expression of related target genes [ 9 , [17] , [18] , [19] , [20] , [21] , [22] , [23] ]. Of stinking note, Nrf2 can also exert a protective effect on normal cells against chemical carcinogens, but rather promotes cancer development and progression, particularly when it is hyper-activated for a long term [ 24 , 25 ].…”

Circadian Oscillation Pattern of Endoplasmic Reticulum Quality Control (ERQC) Components in Human Embryonic Kidney HEK293 Cells

“…Furthermore, it is essential for the ERAD of gamma-aminobutyric acid (GABA) B (GABAB) receptor, nuclear factor erythroid 2-related factor 2 (Nrf2), Parkin-associated endothelial receptor-like receptor (Pael-R), mutant tyrosinase and z-variant antitrypsin (AAT). Additionally, it has been reported that Hrd1 is responsible for the regulation of steady-state levels of ERN1 (ER to Nucleus Signaling-1), NFE2L1 (Nuclear Factor, Erythroid 2 Like 1), MAPT (microtubule-associated protein tau), cytosolic p53 and polyglutamine-extended Huntington protein (polyQ-Htt) [ 38 39 40 41 42 43 44 45 46 ]. Considering to critical roles of ERQC on cellular physiology, it is important to characterize its connection with the circadian rhythm and to show its possible regulatory roles on this molecular clock.…”

CNC-bZIP protein NFE2L1 regulates osteoclast differentiation in antioxidant-dependent and independent manners

“…Previous studies demonstrate that L-NFE2L1 plays crucial roles in the recovery of proteasome activity, antioxidant and inflammation response and adipogenesis [ 11 , 17 , 18 , [55] , [56] , [57] ]. Stable silencing of L-Nfe2l1 in RAW cells resulted in M1 polarization, indicating that L-NFE2L1 functions as a negative regulator of M1 polarization and pro-inflammatory response in macrophages [ 17 ].…”

“…Nuclear factor-erythroid 2-related factor 1 (NFE2L1, commonly symbolized as Nrf1; human analogs are also termed as TCF11 or LCR-F1) is a member of the CNC-bZIP transcription factor family. Human and mouse NFE2L1 genes can be transcribed into alternatively-spliced forms, resulting in multiple protein isoforms [ 11 , 12 ]. NFE2L1 exerts its transcriptional control on genes harboring the NF-E2/AP1-like ARE/EpRE site by forming heterodimers with small musculoaponeurotic fibrosarcoma (sMAF) proteins, subunits of AP-1 or other bZIP proteins [ 13 , 14 ].…”