What is the nrf2 protein

Recent evidence shows that Nrf2 is involved in the control of energy metabolism and might be a promising therapeutic target for obesity. The underlying mechanism of Nrf2 in obesity has been investigated using various experimental approaches, including Nrf2 gene deletion, Nrf2 pharmacological activators and Nrf2 gene overexpression, but only few of these approaches were clinically tested.

Specific pharmacological activators of Nrf2, including epigallocatechin 3-gallate, oltipraz, sulforaphane, curcumin and 1-[2-cyano-3, dioxooleana-1, 9 11 -dienoyl] imidazole CDDO-Im , induce the expression and activity of Nrf2 both in vitro and in vivo Shin et al. The epigallocatechin 3-gallate-induced activation of Nrf2 in liver and adipose tissue of obese mice improves lipidemic control, decreases oxidative products generation, and reduces body mass, insulin and glucose levels Sampath et al.

Interestingly, knockout mice for the Keap-1 protein exhibit similar features, including suppression of high-fat diet-induced obesity and decreased deposition of lipids and cholesterol in the liver Slocum et al.

Of importance, improvement of metabolic profile is closely associated with improved cardiovascular function da Costa et al. A recent study demonstrated that the Nrf2 activator sulforaphane, during revascularization procedures in metabolically compromised individuals, has the potential to suppress the progression of intimal hyperplasia. In addition, Nrf2 activation attenuates leptin-induced proliferation of VSMCs in the diet-induced obesity scenario Shawky et al. Natural compounds are also promising elements in Nrf2 activation during obesity.

As an example, Zeng et al. Similarly, high-fat diet induced oxidative stress, inflammation, fibrosis, hypertrophy and tissue remodeling are attenuated by curcumin treatment. These benefits are closely associated with increased Nrf2 expression and activity, as well as reduced ROS generation Zeng et al. Deletion of the Nrf2 gene is expected to increase ROS generation and to aggravate the phenotypes of obesity. Nrf2 knockout mice show increased ROS generation, deposition of fatty acids in the liver and increased expression of genes related to the synthesis of lipids and cholesterol Tanaka et al.

Consistent with these findings, our group showed that obesity in mice favors vascular oxidative stress by increasing the expression of the downregulatory proteins of Nrf2, Keap-1 and Bach-1 Costa et al.

Nrf2 in adipose tissue function and metabolic syndrome has also been examined. Xue et al. In obese mice, ablation of Nrf2, globally or specifically in adipocytes, reduces white adipose tissue mass. However, Nrf2 deletion results in even more severe metabolic syndrome with aggravated insulin resistance, hyperglycemia, and hypertriglyceridemia.

In addition, when compared to wild-type mice, the white adipose tissue of obese mice expresses substantially higher levels of many genes related to antioxidant response, inflammation, adipogenesis, lipogenesis, glucose uptake, and lipid transport Xue et al. These findings support a role for Nrf2 in regulating adipose tissue development and function, insulin sensitivity, glucose and lipid homeostasis.

In contrast to the above-mentioned study, Nrf2 knockout mice treated with a high-fat diet tend to gain less body mass and display increased insulin sensitivity and glucose tolerance. In addition, they do not exhibit increased glucose, cholesterol, or plasma triglycerides.

Of importance, the altered metabolic phenotype of Nrf2- knockout mice on high-fat diet is associated with higher expression and abundance of fibroblast growth factor 21 FGF21 , a novel hormone that regulates energy metabolism, glucose tolerance and adipose tissue expansion Chartoumpekis et al.

The complex roles of Nrf2 in adipogenesis and adipose tissue functions were recently examined by adipose tissue-specific ablation of Nrf2 in mice. This condition is associated with a transient delayed increase of body weight in high-fat diet-fed mice. However, the benefit is eventually suppressed after prolonged feeding. The phenotypic changes induced by adipose tissue-specific ablation of Nrf2 also extend to the whole-body level, reducing blood glucose and altering the expression of genes involved in glucose, lipid and energy metabolism Zhang et al.

These findings are consistent with those of previous studies using Nrf2 knockout mice Pi et al. To date there are no studies showing direct effects of Nrf2 deletion on cardiovascular function. The apparent contradictory role of Nrf2 protecting mice from obesity and insulin resistance in conditions of Nrf2 deficiency in comparison to Nrf2 pharmacological activation, may be explained by the observations that Nrf2 deficiency leads to a mild increase in the levels of ROS, which stimulate the antioxidant system in a manner similar to the Nrf2 activators reviewed in Bocci et al.

Another possible explanation is that Nrf2 activators also regulate non-Nrf2 signaling pathways to modulate glucose and lipid metabolism. The same is true for Keap-1, the Nrf2 repressor protein, which may also have Nrf2-independent effects on transcription factors and, consequently, on metabolic homeostasis Huang et al.

Controversial results on the role of Nrf2 in obesity may be linked to differences in the pathophysiological characteristics of obesity such as diet content or time under obesity conditions , as well as specific genetic characteristics. Table 1 summarizes the contribution of Nrf2 signaling in different obesity conditions. Further studies are required to explore this apparent discrepancy on the role of Nrf2 in obesity. Table 1. Nrf2 signaling and actions in obesity and atherosclerosis animals models.

The intestinal microbiome and its metabolites display a pivotal role in host physiological processes including immune, metabolic, neurological, and nutritional homeostasis reviewed in Lynch and Pedersen, Many of these physiological processes are under influence of ROS generation in the gut epithelia.

In addition, the relationship between bacterial-dependent ROS generation and Nrf2 pathway activity was recently revealed by observations that lactobacilli-induced and Nox1-mediated generation of ROS evokes Nrf2-dependent activation of cytoprotective antioxidants genes Jones et al. There is abundant evidence that oxidative damage caused by free radicals contributes to the pathogenesis and progression of type 2 diabetes mellitus and its complications reviewed in Dandona et al.

Furthermore, as noted in an excellent and recent review on Nrf2 David et al. There are promising results provided by animal studies and clinical trials suggesting that activation of this pathway can delay or even reverse type 2 diabetes mellitus-associated dysfunctions Ichikawa et al.

A consistent alteration in diabetic patients is the presence of endothelial dysfunction, which precedes the development of diabetes-associated vascular complications and may explain, in part, the increased cardiovascular risk in this condition. Endothelial dysfunction in diabetes is associated with enhanced vascular contractility, oxidative stress and vascular inflammation Zakkar et al.

The importance of Nrf2 and its downstream elements in the control of vascular function in diabetes has become increasingly apparent and is reinforced by multiple studies using many of the same agents for protection from conditions other than diabetes. Its therapeutic potential was extended to clinical trials in type 2 diabetic patients with chronic kidney disease Pergola et al.

Considering that endothelial dysfunction, which is the first step in the development of vascular complications in diabetes, is accompanied by pro-oxidative and pro-inflammatory processes, the atheroprotective effects of dh could be mediated by improvement of the endothelial function. In agreement with these observations, increased Nrf2 activity induced, for example, by bardoxolone or sulforaphane, abrogates augmented vascular contraction Alves-Lopes et al.

Other mechanisms include reduced systemic and vascular oxidative stress as well as increased nitric oxide NO bioavailability Liu et al.

Beyond this immediate homeostatic response, long-term consequences of Nrf2 activity have also been described as important culprits of micro-and macrovascular complications associated with diabetes.

This implies that Nrf2 modulates many cellular activities, beyond its immediate homeostatic and cytoprotective actions, influencing processes as diverse as inflammation, proliferation, apoptosis, cell differentiation, tissue regeneration and even metabolism. In fact, decreased activation of Nrf2 is observed in experimental diabetic cardiomyopathy, along with a decrease in the downstream activity of antioxidant enzymes and increased oxidative stress Wang et al.

In this sense, activation of the Nrf2 system attenuates vascular remodeling by decreasing proliferation, migration, and fibrotic processes. Such widespread protective effects of Nrf2 might constitute the underlying mechanism involved in the progression of diabetes-associated complications. These results have also provided strong support for the development of new potent enhancers of Nrf2 activity for the prevention and treatment of many diseases in which both inflammatory and oxidative processes have a key pathogenic role.

Atherosclerosis, a progressing inflammatory disease produced by many risk factors, such as diabetes, hypertension, and hyperlipidemia, is one of the major cardiovascular diseases, which, together with myocardial infarction and coronary heart disease, will account for more than 20 million deaths in reviewed in Yahagi et al.

Even though much is known about the mechanisms that result in the formation of atherosclerotic plaque, the processes are not entirely understood. During the atherogenesis process, the build-up of lipids in the arterial intima triggers several changes in the microenvironment of the arterial wall, such as the formation of fatty streaks, endothelial dysfunction, recruitment and activation of immune cells and VSMCs proliferation reviewed in Raggi et al.

Recruitment and retention of inflammatory cells lead to persistent production of cytokines and ROS that contribute to the progression of atherosclerotic lesion reviewed in Koelwyn et al.

Increased ROS induces the oxidation of low-density lipoprotein LDL to ox-LDL that contributes to oxidative stress and foam cell formation in the arterial wall, aggravating the atherosclerotic plaque formation reviewed in Koelwyn et al.

For instance, deficiency of GPX-1, a Nrf2 target gene, in mice increases ox-LDL-induced foam cell formation and leads to amplified proliferative activity of peritoneal macrophages, indicating that this gene is atheroprotective Cheng et al. Moreover, atherosclerotic lesion development and oxidative stress are accelerated in HO-1 deficient ApoE knockout mice Yet et al. Deletion of HO-1 in macrophages increases lipid build-up and foam cell formation and, consequently, the production of ROS and pro-inflammatory cytokines Orozco et al.

Cheng et al. These findings indicate that HO-1 is a major regulator of advanced atherosclerotic lesion progression Cheng et al. However, it is not clear whether the induction of HO-1 is a compensatory atheroprotective response, trying to reduce increased levels of ROS in the plaque, or if it contributes to increased plaque vulnerability.

Therefore, more studies are necessary to understand the role of HO-1 in advanced atherosclerotic plaque stage. On the other hand, Nrf2 gene deletion in ApoE knockout mice decreases atherosclerotic lesions at a late stage, whereas it does not affect atherosclerotic lesions in earlier stages Harada et al.

These observations suggest that Nrf2 inhibition may be atheroprotective in advanced plaques. Additionally, Ishii et al. These conflicting findings demonstrate that Nrf2 may also exhibit pro-atherogenic functions, depending on atherosclerotic lesion stage or animal model.

The accumulation of lipids into the vascular intima is related to oxidative and pro-inflammatory stress that result in endothelial cells dysfunction reviewed in Sitia et al.

Pro-inflammatory cytokines contribute to monocytes recruitment into the intima by inducing expression of endothelial adhesion molecules and chemokines.

Nrf2 activity reduces the inflammatory response in endothelial cells. These results indicate that Nrf2 activation is atheroprotective due to its antioxidant and anti-inflammatory actions that limit the deleterious effects imposed by hyperlipidemic and inflammatory processes to endothelial cells.

Nrf2 anti-atherogenic effects have also been linked to its modulatory effects on migration and proliferation of VSMCs. Taken together, these studies indicate that Nrf2 may protect against atherogenesis by decreasing VSMCs migration, proliferation, calcification and vascular remodeling. In recent years, microRNAs non-coding small RNAs were identified as key regulators in the cellular events and molecular signaling pathways involved in atherosclerosis reviewed in Feinberg and Moore, Multiple microRNAs that participate in cholesterol homeostasis miR , macrophage activation miR , endothelium dysfunction miR , VSMCs proliferation miR , and other processes that lead to plaque progression have already been identified reviewed in Feinberg and Moore, In this context, the Nrf2 system and microRNAs can establish regulatory loops and influence vascular responses to oxidative and inflammatory injury.

Moreover, oxidized palmitoyl-arachidonoyl-phosphatidylcholine Ox-PAPC - induced HO-1 expression is partially dependent on miRa in endothelial cells Schrottmaier et al. However, the role of microRNAs in the Nrf2 system and their implications in atherogenesis need to be further explored.

In conclusion, anti-oxidant and anti-inflammatory effects of Nrf2 play an essential modulatory role in the formation and progression of atherosclerotic lesions, regulating functional and structural vascular responses. However, additional studies are necessary to explain the discrepant results related to the role of Nrf2 in the different stages of plaque progression.

The interactions between microRNAs and Nrf2 target genes during atherosclerosis development also deserve further investigation. Activation of the Nrf2-dependent antioxidant system plays an important role in cell defense against oxidative stress damage, whereas the insufficiency of the Nrf2 system is associated with multiple aspects of the genesis and progression of metabolic diseases, posing a great risk to the cardiovascular system Figure 1.

The systemic increase of Nrf2 activity by several activators may be beneficial in the treatment of metabolic diseases.

In addition, selective upregulation of Nrf2 genes may represent a potential therapy in obesity, diabetes and atherosclerosis. Looking to the future, experimental research that elucidates the role of Nrf2 activation in specific tissues, such as adipose tissue, liver, pancreas and others, is important for better understanding of the multiple roles of Nrf2. Additional studies may also provide new redox balance-targeted therapy for the treatment of metabolic diseases and consequent mitigation of cardiovascular risk.

Figure 1. Mechanisms involved in the actions of reactive oxygen species that lead to metabolic diseases and cardiovascular risk development. Metabolic diseases are closely associated with increased generation of reactive oxygen species ROS due to reduced Nrf2 antioxidant activity. This phenomenon culminates in target-organ damage and metabolism disorders, such as adipogenesis and adipose tissue inflammation, increased production of hepatic cholesterol, decreased insulin secretion, insulin resistance, loss of integrity of vascular tone control, endothelial dysfunction and atheroma formation, all contributing to increased cardiovascular risk.

Nrf2 activation by several agents reduces ROS levels, decreasing metabolic damage and reducing cardiovascular risk. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Abed, D. Discovery of direct inhibitors of Keap1—Nrf2 protein—protein interaction as potential therapeutic and preventive agents.

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Renal Physiol. Follow Gene Phenotype Search. Added to MyGenes. Email me updates on this gene. Manage MyGenes. Cancel OK. Jump to section. Antibodies Assays Proteins Inhib. Multiple tr See more Transcription factor that plays a key role in the response to oxidative stress: binds to antioxidant response ARE elements present in the promoter region of many cytoprotective genes, such as phase 2 detoxifying enzymes, and promotes their expression, thereby neutralizing reactive electrophiles PubMed, PubMed, PubMed, PubMed May also be involved in the transcriptional activation of genes of the beta-globin cluster by mediating enhancer activity of hypersensitive site 2 of the beta-globin locus control region PubMed Interacts with CHD6; involved in activation of the transcription By similarity.

Predicted three dimensional structure from AlphaFold Q Abcam antibodies for NFE2L2. Biorbyt antibodies for NFE2L2. Abcam proteins for NFE2L2.

Abcam assays for NFE2L2. Browse Sino Biological Assays. Belongs to the bZIP family. CNC subfamily. Family: Belongs to the bZIP family. Bhide, S. Increasing autophagy and blocking Nrf2 suppress laminopathy-induced age-dependent cardiac dysfunction and shortened lifespan. Aging Cell 17, e Bhuiyan, M. Enhanced autophagy ameliorates cardiac proteinopathy. Chen, Q. Nrf2 at the heart of oxidative stress and cardiac protection. Genomics 50, 77— Cohn, J. Cardiac remodeling—concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling.

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