Bach1 Deficiency Ameliorates Hepatic Injury in a Mouse Model

Iida, Akio; Inagaki, Koji; Miyazaki, Akira; Yonemori, Fumihiko; Ito, Etsuro; Igarashi, Kazuhiko

doi:10.1620/tjem.217.223

Cited by 20 publications

(17 citation statements)

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“…We need to examine whether Bach1 deficiency modulates ROS metabolism when mice are challenged with oxidative stress. The results suggest that a targeting of Bach1 in medical treatment is acceptable for acute and chronic injuries without any long-term side effect as shown in several papers [1, 26, 28, 29, 31, 45]. …”

Section: Resultsmentioning

confidence: 55%

“…Despite the growing number of evidences that inhibition of Bach1 may be beneficial in certain clinical situations [1, 26, 28, 29, 31, 45], the long-term, organismal response to Bach1 ablation has not yet been examined. Considering its distinct effects on ROS homeostasis and cell proliferation, Bach1 deficiency may affect the aging and/or life span in mice under normal conditions; ROS levels would decrease via the derepression of HO-1, and/or the p53-dependent cellular senescence would be increased by the enhanced activity of p53.…”

Section: Introductionmentioning

confidence: 99%

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Bach1Deficiency and Accompanying Overexpression of Heme Oxygenase-1 Do Not Influence Aging or Tumorigenesis in Mice

Ota

Brydun

Itoh-Nakadai

et al. 2014

Oxidative Medicine and Cellular Longevity

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Oxidative stress contributes to both aging and tumorigenesis. The transcription factor Bach1, a regulator of oxidative stress response, augments oxidative stress by repressing the expression of heme oxygenase-1 (HO-1) gene (Hmox1) and suppresses oxidative stress-induced cellular senescence by restricting the p53 transcriptional activity. Here we investigated the lifelong effects of Bach1 deficiency on mice. Bach1-deficient mice showed longevity similar to wild-type mice. Although HO-1 was upregulated in the cells of Bach1-deficient animals, the levels of ROS in Bach1-deficient HSCs were comparable to those in wild-type cells. Bach1 −/−; p53 −/− mice succumbed to spontaneous cancers as frequently as p53-deficient mice. Bach1 deficiency significantly altered transcriptome in the liver of the young mice, which surprisingly became similar to that of wild-type mice during the course of aging. The transcriptome adaptation to Bach1 deficiency may reflect how oxidative stress response is tuned upon genetic and environmental perturbations. We concluded that Bach1 deficiency and accompanying overexpression of HO-1 did not influence aging or p53 deficiency-driven tumorigenesis. Our results suggest that it is useful to target Bach1 for acute injury responses without inducing any apparent deteriorative effect.

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Section: Resultsmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Bach1Deficiency and Accompanying Overexpression of Heme Oxygenase-1 Do Not Influence Aging or Tumorigenesis in Mice

Ota

Brydun

Itoh-Nakadai

et al. 2014

Oxidative Medicine and Cellular Longevity

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“…Although advances toward understanding the involvement of Bach1 in cytoprotection during liver and myocardial ischemia have been made, 40,41 the biologic role of the CNC member Bach1 is still largely unknown. Here, we show that, in addition to Bach1-mediated normal programming of APC development, it plays a role in generating optimal immunity and autoimmune-related pathology.…”

Section: Discussionmentioning

confidence: 99%

Regulation of APC development, immune response, and autoimmunity by Bach1/HO-1 pathway in mice

Garcia-Flores

Minisandram

et al. 2012

Blood

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IntroductionAbnormal development of APCs can result in immunodeficiency and autoimmune disease. APCs, which include macrophages, B cells, and dendritic cells (DCs), and are critical for mediating adaptive immunity to foreign antigens as well as inducing tolerance to self-antigens. At steady state, macrophages are generated from monocytes, and classic DCs are derived from their precursor (pre-cDCs) and common DC progenitors (CDPs). [1][2][3][4][5][6] These cells are all generated from upstream macrophage-DC precursor (MDP) cells, 7-9 which are themselves derived from less lineage-restricted common myeloid progenitors (CMPs). 1 The entire populations of hematopoietic cells originate from pluripotent HSCs in the BM (see Figure 7A). Despite recent advances, the cellular factors that regulate the progression of HSCs to the development of APCs remain largely uncharacterized.Cap 'n' collar (CNC) proteins are evolutionarily conserved factors that are known to be essential for the resolution of oxidative stress. 10 In Caenorhabditis elegans, the CNC protein SKN-1 regulates longevity. 11,12 In mammals, there are 6 members within the CNC family (p45, Nrf1, Nrf2, Nrf3, Bach1, and Bach2) that heterodimerize with small Maf proteins (MafK, MafG, and MafF) to direct either gene induction or repression. 13 For instance, although the co-occupancy of p45 and MafK at genome elements activates transcription, binding of a Bach1 and MafK heterodimer to these elements results in gene repression. 14 Many different CNC and Maf heterodimers are formed, 15 causing the biology of CNC and Maf members to be complex. Although Nrf1 Ϫ/Ϫ mice are anemic and have embryonic or postnatal lethality, 16 ablation of p45 in mice leads to defective platelet production. 17 Although deletion of Bach2 in mice caused impaired antibody class switching, 18 disruption of Nrf2 resulted in a neurodegenerative disorder and autoimmune disease. [19][20][21] Deciphering the physiologic role of some of the CNC/Maf proteins has also proven to be challenging because of the potential functional redundancy among them. 22,23 The CNC/Maf network has been associated with a myriad of human disorders, including those of the skin, respiratory system, and hematopoietic system. 10,15,24 Thus, drug therapy involving the CNC pathway is actively being studied in humans for cancer chemoprevention, inflammatory diseases, and autoimmune diseases (for review, see Sykiotis and Bohmann 10 ). For example, the fumaric acid ester dimethylfumarate, which exerts neuroprotection by inducing Nrf2 expression, is currently in a phase 3 clinical trial as an orally active effective treatment of human multiple sclerosis with limited side effects. 25,26 Thus, deciphering the functions of the individual CNC subunits will not only be crucial to unraveling the overlapping and unique functions of these proteins but also provide insights to the potential of targeting CNC proteins for therapy against relevant diseases. In particular, the CNC member Bach1 is up-regulated in fetal Down syndrome (DS) brain. ...

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“…system/organ effects of Bach1-deficiency references blood vessel reduction of cuff injyury with reduced smooth muscle proliferation (Omura et al, 2005) reduction in atherosclerosis in Apo E kockout mice ) heart reduction in I/R injury (Yano et al, 2006) reduced hypertrophy after pressure overload lung reduced damages after high oxygen exposure (Tanimoto et al, 2009) intestine reduced injury in small intestine after indomethacin administration (Harusato et al, 2011;Harusato et al, 2009) reduction in trinitrobenzene sulfonic acid (TNBS)-induced colitis (Harusato et al, 2013) liver reduction in steatohepatitis induced by methionine-choline deficient diet reduced damages induced by D-galactosamine and lipopolysaccharide (Iida et al, 2009) pancreas reduction of apoptosis of beta cells and less increase of blood glucose upon alloxan treatment (Kondo et al, 2013) intervertebral disc reduced damages in annulus puncture model (Ochiai et al, 2008) spinal cord reduced damages after mechanical injury and better locomoter activity (Kanno et al, 2009;Yamada et al, 2008) type mice and reduced areas of infarction after I/R (Yano et al 2006). Cardiac hypertrophy is a compensatory mechanism of the heart that functions to maintain cardiac output in the presence of sustained increases in the hemodynamic load, although it can lead to the development of cardiac failure.…”

Section: Bach1 As a Potential Therapeutic Target In Oxidative Stressrmentioning

confidence: 99%

“…In this model, Bach1-deficient mice exhibit negligible amounts of hepatic steatosis compared to the pronounced steatohepatitis observed in wild-type mice . Liver injury induced by the combination of D-galactosamine (GalN) and lipopolysaccharide (LPS) has also been reported to be reduced in Bach1-deficient mice (Iida et al 2009). …”

Section: Bach1 As a Potential Therapeutic Target In Oxidative Stressrmentioning

confidence: 99%

Wearing Red for Signaling: The Heme-Bach Axis in Heme Metabolism, Oxidative Stress Response and Iron Immunology

Igarashi

Watanabe-Matsui

2014

Tohoku J. Exp. Med.

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102

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The connection between gene regulation and metabolism is an old issue that warrants revisiting in order to understand both normal as well as pathogenic processes in higher eukaryotes. Metabolites affect the gene expression by either binding to transcription factors or serving as donors for post-translational modification, such as that involving acetylation and methylation. The focus of this review is heme, a prosthetic group of proteins that includes hemoglobin and cytochromes. Heme has been shown to bind to several transcription factors, including Bach1 and Bach2, in higher eukaryotes. Heme inhibits the transcriptional repressor activity of Bach1, resulting in the derepression of its target genes, such as globin in erythroid cells and heme oxygenase-1 in diverse cell types. Since Bach2 is important for class switch recombination and somatic hypermutation of immunoglobulin genes as well as regulatory and effector T cell differentiation and the macrophage function, the heme-Bach2 axis may regulate the immune response as a signaling cascade. We discuss future issues regarding the topic of the iron/heme-gene regulation network based on current understanding of the heme-Bach axis, including the concept of "iron immunology" as the synthesis of the iron metabolism and the immune response.

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Bach1 Deficiency Ameliorates Hepatic Injury in a Mouse Model

Cited by 20 publications

References 50 publications

Bach1Deficiency and Accompanying Overexpression of Heme Oxygenase-1 Do Not Influence Aging or Tumorigenesis in Mice

Bach1Deficiency and Accompanying Overexpression of Heme Oxygenase-1 Do Not Influence Aging or Tumorigenesis in Mice

Regulation of APC development, immune response, and autoimmunity by Bach1/HO-1 pathway in mice

Wearing Red for Signaling: The Heme-Bach Axis in Heme Metabolism, Oxidative Stress Response and Iron Immunology

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