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Sultana M, Islam MA, Khairnar R, Kumar S. A guide to pathophysiology, signaling pathways, and preclinical models of liver fibrosis. Mol Cell Endocrinol 2025; 598:112448. [PMID: 39755140 DOI: 10.1016/j.mce.2024.112448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/23/2024] [Accepted: 12/28/2024] [Indexed: 01/06/2025]
Abstract
Liver fibrosis is potentially a reversible form of liver disease that evolved from the early stage of liver scarring as a consequence of chronic liver injuries. Recurrent injuries in the liver without any appropriate medication cause the injuries to get intense and deeper, which gradually leads to the progression of irreversible cirrhosis or carcinoma. Unfortunately, there are no approved treatment strategies for reversing hepatic fibrosis, making it one of the significant risk factors for developing advanced liver disorders and liver disease-associated mortality. Consequently, the interpretation of the fundamental mechanisms, etiology, and pathogenesis is crucial for identifying the potential therapeutic target as well as evaluating novel anti-fibrotic therapy. However, despite innumerable research, the functional mechanism and disease characteristics are still obscure. To accelerate the understanding of underlying disease pathophysiology, molecular pathways and disease progression mechanism, it is crucial to mimic human liver disease through the formation of precise disease models. Although various in vitro and in vivo liver fibrotic models have emerged and developed already, a perfect clinical model replicating human liver diseases is yet to be established, which is one of the major challenges in discovering proper therapeutics. This review paper will shed light on pathophysiology, signaling pathways, preclinical models of liver fibrosis, and their limitations.
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Affiliation(s)
- Mehonaz Sultana
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Md Asrarul Islam
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Rhema Khairnar
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Sunil Kumar
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
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2
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Suzauddula M, Islam MN, Ahmed T. The complex role of glycine N-methyltransferase in metabolism-a review. Mol Biol Rep 2025; 52:271. [PMID: 40025311 DOI: 10.1007/s11033-025-10374-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 02/19/2025] [Indexed: 03/04/2025]
Abstract
BACKGROUND Glycine N-methyltransferase (GNMT) is an enzyme predominantly found in the liver, playing a crucial role in various metabolic pathways. GNMT is involved in transmethylation, transsulfuration, one-carbon metabolism, energy metabolism, and DNA methylation. Deletion or Knockdown of GNMT influences the expression of several key metabolic enzymes by accumulating S-adenosylmethionine (SAM). Dysregulation of GNMT and these metabolic enzymes can lead to metabolic dysfunction and chronic diseases. OBJECTIVE To provide a comprehensive review of the impact of Glycine N-methyltransferase (GNMT) on metabolism, focusing on its epigenetic and genetic mechanisms, its role in metabolic pathways, and its association with chronic diseases. RESULTS GNMT is highly expressed in the liver and exerts direct and indirect effects on various metabolic pathways, including transmethylation, transsulfuration, one-carbon metabolism, energy metabolism, and global DNA methylation. Current understanding suggests that GNMT operates through both epigenetic and genetic mechanisms, influencing the expression of key metabolic enzymes such as BHMT, NNMT, PEMT, DNMTs, CBS, and MTHFR through the accumulation of S-adenosylmethionine. Dysregulation of these proteins not only affects metabolic function but also contributes to the development of several chronic diseases. Furthermore, the level of GNMT protein has been directly linked to non-alcoholic fatty liver disease, with its function being gender, age, and organ specific. At the same time, GNMT and disease progression correlate, dietary supplementation and pharmacological approaches have shown promise in controlling GNMT levels. CONCLUSION GNMT plays a multifaceted role in metabolism, influencing various pathways and contributing to chronic disease development. Understanding its mechanisms and interactions opens avenues for targeted dietary and pharmacological therapies to manage GNMT-related metabolic dysfunction.
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Affiliation(s)
- Md Suzauddula
- Department of Nutrition and Food Engineering, Daffodil International University, Dhaka, Bangladesh
| | - Md Numan Islam
- Department of Nutrition and Food Technology, Jashore University of Science and Technology, Jashore, 7408, Bangladesh
| | - Tanvir Ahmed
- Department of Food Engineering & Tea Technology, Shahjalal University of Science & Technology, Sylhet, Bangladesh.
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3
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Fernández-Ramos D, Lopitz-Otsoa F, Lu SC, Mato JM. S-Adenosylmethionine: A Multifaceted Regulator in Cancer Pathogenesis and Therapy. Cancers (Basel) 2025; 17:535. [PMID: 39941901 PMCID: PMC11816870 DOI: 10.3390/cancers17030535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 01/30/2025] [Accepted: 02/03/2025] [Indexed: 02/16/2025] Open
Abstract
S-adenosylmethionine (SAMe) is a key methyl donor that plays a critical role in a variety of cellular processes, such as DNA, RNA and protein methylation, essential for maintaining genomic stability, regulating gene expression and maintaining cellular homeostasis. The involvement of SAMe in cancer pathogenesis is multifaceted, as through its multiple cellular functions, it can influence tumor initiation, progression and therapeutic resistance. In addition, the connection of SAMe with polyamine synthesis and oxidative stress management further underscores its importance in cancer biology. Recent studies have highlighted the potential of SAMe as a biomarker for cancer diagnosis and prognosis. Furthermore, the therapeutic implications of SAMe are promising, with evidence suggesting that SAMe supplementation or modulation could improve the efficacy of existing cancer treatments by restoring proper methylation patterns and mitigating oxidative damage and protect against damage induced by chemotherapeutic drugs. Moreover, targeting methionine cycle enzymes to both regulate SAMe availability and SAMe-independent regulatory effects, particularly in methionine-dependent cancers such as colorectal and lung cancer, presents a promising therapeutic approach. Additionally, exploring epitranscriptomic regulations, such as m6A modifications, and their interaction with non-coding RNAs could enhance our understanding of tumor progression and resistance mechanisms. Precision medicine approaches integrating patient subtyping and combination therapies with chemotherapeutics, such as decitabine or doxorubicin, together with SAMe, can enhance chemosensitivity and modulate epigenomics, showing promising results that may improve treatment outcomes. This review comprehensively examines the various roles of SAMe in cancer pathogenesis, its potential as a diagnostic and prognostic marker, and its emerging therapeutic applications. While SAMe modulation holds significant promise, challenges such as bioavailability, patient stratification and context-dependent effects must be addressed before clinical implementation. In addition, better validation of the obtained results into specific cancer animal models would also help to bridge the gap between research and clinical practice.
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Affiliation(s)
- David Fernández-Ramos
- Precision Medicine and Metabolism Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Spain; (D.F.-R.); (F.L.-O.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Fernando Lopitz-Otsoa
- Precision Medicine and Metabolism Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Spain; (D.F.-R.); (F.L.-O.)
| | - Shelly C. Lu
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
| | - José M. Mato
- Precision Medicine and Metabolism Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Spain; (D.F.-R.); (F.L.-O.)
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Tan EY, Muthiah MD, Sanyal AJ. Metabolomics at the cutting edge of risk prediction of MASLD. Cell Rep Med 2024; 5:101853. [PMID: 39657668 PMCID: PMC11722125 DOI: 10.1016/j.xcrm.2024.101853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 10/12/2024] [Accepted: 11/14/2024] [Indexed: 12/12/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major public health threat globally. Management of patients afflicted with MASLD and research in this domain are limited by the lack of robust well-established non-invasive biomarkers for diagnosis, prognostication, and monitoring. The circulating metabolome reflects both the systemic metabo-inflammatory milieu and changes in the liver in affected individuals. In this review we summarize the available literature on changes in the different components of the metabolome in MASLD with a focus on changes that are linked to the presence of underlying steatohepatitis, severity of disease activity, and fibrosis stage. We further summarize the existing literature around biomarker panels that are derived from interrogation of the metabolome. Their relevance to disease biology and utility in practice are also discussed. We further highlight potential direction for future studies particularly to ensure they are fit for purpose and suitable for widespread use.
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Affiliation(s)
- En Ying Tan
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore.
| | - Mark D Muthiah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Arun J Sanyal
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
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Sun WD, Zhu XJ, Li JJ, Mei YZ, Li WS, Li JH. Nicotinamide N-methyltransferase (NNMT): A key enzyme in cancer metabolism and therapeutic target. Int Immunopharmacol 2024; 142:113208. [PMID: 39312861 DOI: 10.1016/j.intimp.2024.113208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 09/17/2024] [Accepted: 09/17/2024] [Indexed: 09/25/2024]
Abstract
Emerging research has positioned Nicotinamide N-methyltransferase (NNMT) as a key player in oncology, with its heightened expression frequently observed across diverse cancers. This increased presence is tightly linked to tumor initiation, proliferation, and metastasis. The enzymatic function of NNMT is centered on the methylation of nicotinamide (NAM), utilizing S-adenosylmethionine (SAM) as the methyl donor, which results in the generation of S-adenosyl-L-homocysteine (SAH) and methyl nicotinamide (MNAM). This metabolic process reduces the availability of NAM, necessary for Nicotinamide adenine dinucleotide (NAD+) synthesis, and generates SAH, precursor to homocysteine (Hcy). These alterations are theorized to foster the resilience, expansion, and invasiveness of cancer cells. Furthermore, NNMT is implicated in enhancing cancer malignancy by affecting multiple signaling pathways, such as phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT), cancer-associated fibroblasts (CAFs) and 5-Methyladenosine (5-MA), epithelial-mesenchymal transition (EMT), and epigenetic mechanisms. Upregulation of NNMT metabolism plays a key role in the formation and maintenance of the tumour microenvironment. While the use of small molecule inhibitors and RNA interference (RNAi) to target NNMT has shown therapeutic promise, the full extent of NNMT's influence on cancer is not yet fully understood, and clinical evidence is limited. This article systematically describes the relationship between the functional metabolism of NNMT enzymes and the cancer and tumour microenvironments, describing the mechanisms by which NNMT contributes to cancer initiation, proliferation, and metastasis, as well as targeted therapies. Additionally, we discuss the future opportunities and challenges of NNMT in targeted anti-cancer treatments.
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Affiliation(s)
- Wei-Dong Sun
- Key Lab of Aquatic Training Monitoring and Intervention of General Administration of Sport of China, Physical Education College, Jiangxi Normal University, Nanchang 330022, Jiangxi Province, China
| | - Xiao-Juan Zhu
- Key Lab of Aquatic Training Monitoring and Intervention of General Administration of Sport of China, Physical Education College, Jiangxi Normal University, Nanchang 330022, Jiangxi Province, China
| | - Jing-Jing Li
- Key Lab of Aquatic Training Monitoring and Intervention of General Administration of Sport of China, Physical Education College, Jiangxi Normal University, Nanchang 330022, Jiangxi Province, China
| | - Ya-Zhong Mei
- Key Lab of Aquatic Training Monitoring and Intervention of General Administration of Sport of China, Physical Education College, Jiangxi Normal University, Nanchang 330022, Jiangxi Province, China
| | - Wen-Song Li
- Key Lab of Aquatic Training Monitoring and Intervention of General Administration of Sport of China, Physical Education College, Jiangxi Normal University, Nanchang 330022, Jiangxi Province, China
| | - Jiang-Hua Li
- Key Lab of Aquatic Training Monitoring and Intervention of General Administration of Sport of China, Physical Education College, Jiangxi Normal University, Nanchang 330022, Jiangxi Province, China.
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Fuster-Martínez I, Català-Senent JF, Hidalgo MR, Roig FJ, Esplugues JV, Apostolova N, García-García F, Blas-García A. Integrated transcriptomic landscape of the effect of anti-steatotic treatments in high-fat diet mouse models of non-alcoholic fatty liver disease. J Pathol 2024; 262:377-389. [PMID: 38180387 DOI: 10.1002/path.6242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 10/20/2023] [Accepted: 11/28/2023] [Indexed: 01/06/2024]
Abstract
High-fat diet (HFD) mouse models are widely used in research to develop medications to treat non-alcoholic fatty liver disease (NAFLD), as they mimic the steatosis, inflammation, and hepatic fibrosis typically found in this complex human disease. The aims of this study were to identify a complete transcriptomic signature of these mouse models and to characterize the transcriptional impact exerted by different experimental anti-steatotic treatments. For this reason, we conducted a systematic review and meta-analysis of liver transcriptomic studies performed in HFD-fed C57BL/6J mice, comparing them with control mice and HFD-fed mice receiving potential anti-steatotic treatments. Analyzing 21 studies broaching 24 different treatments, we obtained a robust HFD transcriptomic signature that included 2,670 differentially expressed genes and 2,567 modified gene ontology biological processes. Treated HFD mice generally showed a reversion of this HFD signature, although the extent varied depending on the treatment. The biological processes most frequently reversed were those related to lipid metabolism, response to stress, and immune system, whereas processes related to nitrogen compound metabolism were generally not reversed. When comparing this HFD signature with a signature of human NAFLD progression, we identified 62 genes that were common to both; 10 belonged to the group that were reversed by treatments. Altered expression of most of these 10 genes was confirmed in vitro in hepatocytes and hepatic stellate cells exposed to a lipotoxic or a profibrogenic stimulus, respectively. In conclusion, this study provides a vast amount of information about transcriptomic changes induced during the progression and regression of NAFLD and identifies some relevant targets. Our results may help in the assessment of treatment efficacy, the discovery of unmet therapeutic targets, and the search for novel biomarkers. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Isabel Fuster-Martínez
- Departamento de Farmacología, Universitat de València, Valencia, Spain
- FISABIO (Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana), Valencia, Spain
| | - José F Català-Senent
- Computational Biomedicine Laboratory, Principe Felipe Research Center, Valencia, Spain
| | - Marta R Hidalgo
- Computational Biomedicine Laboratory, Principe Felipe Research Center, Valencia, Spain
| | - Francisco J Roig
- Computational Biomedicine Laboratory, Principe Felipe Research Center, Valencia, Spain
- Facultad de Ciencias de la Salud, Universidad San Jorge, Campus Universitario Villanueva de Gállego, Zaragoza, Spain
| | - Juan V Esplugues
- Departamento de Farmacología, Universitat de València, Valencia, Spain
- FISABIO (Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana), Valencia, Spain
- CIBEREHD (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas), Madrid, Spain
| | - Nadezda Apostolova
- Departamento de Farmacología, Universitat de València, Valencia, Spain
- FISABIO (Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana), Valencia, Spain
- CIBEREHD (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas), Madrid, Spain
| | | | - Ana Blas-García
- FISABIO (Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana), Valencia, Spain
- CIBEREHD (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas), Madrid, Spain
- Departamento de Fisiología, Universitat de València, Valencia, Spain
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Castillejo-López C, Bárcenas-Walls JR, Cavalli M, Larsson A, Wadelius C. A regulatory element associated to NAFLD in the promoter of DIO1 controls LDL-C, HDL-C and triglycerides in hepatic cells. Lipids Health Dis 2024; 23:48. [PMID: 38365720 PMCID: PMC10870585 DOI: 10.1186/s12944-024-02029-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 01/22/2024] [Indexed: 02/18/2024] Open
Abstract
BACKGROUND Genome-wide association studies (GWAS) have identified genetic variants linked to fat metabolism and related traits, but rarely pinpoint causative variants. This limitation arises from GWAS not considering functional implications of noncoding variants that can affect transcription factor binding and potentially regulate gene expression. The aim of this study is to investigate a candidate noncoding functional variant within a genetic locus flagged by a GWAS SNP associated with non-alcoholic fatty liver disease (NAFLD), a condition characterized by liver fat accumulation in non-alcohol consumers. METHODS CRISPR-Cas9 gene editing in HepG2 cells was used to modify the regulatory element containing the candidate functional variant linked to NAFLD. Global gene expression in mutant cells was assessed through RT-qPCR and targeted transcriptomics. A phenotypic assay measured lipid droplet accumulation in the CRISPR-Cas9 mutants. RESULTS The candidate functional variant, rs2294510, closely linked to the NAFLD-associated GWAS SNP rs11206226, resided in a regulatory element within the DIO1 gene's promoter region. Altering this element resulted in changes in transcription factor binding sites and differential expression of candidate target genes like DIO1, TMEM59, DHCR24, and LDLRAD1, potentially influencing the NAFLD phenotype. Mutant HepG2 cells exhibited increased lipid accumulation, a hallmark of NAFLD, along with reduced LDL-C, HDL-C and elevated triglycerides. CONCLUSIONS This comprehensive approach, that combines genome editing, transcriptomics, and phenotypic assays identified the DIO1 promoter region as a potential enhancer. Its activity could regulate multiple genes involved in the NAFLD phenotype or contribute to defining a polygenic risk score for enhanced risk assessment in NAFLD patients.
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Affiliation(s)
- Casimiro Castillejo-López
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 08 , Uppsala, Sweden, Box 815, Husargatan 3, BMC
| | - José Ramón Bárcenas-Walls
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 08 , Uppsala, Sweden, Box 815, Husargatan 3, BMC
| | - Marco Cavalli
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 08 , Uppsala, Sweden, Box 815, Husargatan 3, BMC
| | - Anders Larsson
- Department of Medical Sciences, Clinical Chemistry, Uppsala University Hospital, 751 85, Uppsala, Sweden
| | - Claes Wadelius
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 08 , Uppsala, Sweden, Box 815, Husargatan 3, BMC.
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Ntambi JM, Liu X, Burhans MS, ALjohani A, Selen ES, Kalyesubula M, Assadi-Porter F. Hepatic oleate regulates one-carbon metabolism during high carbohydrate feeding. Biochem Biophys Res Commun 2023; 651:62-69. [PMID: 36791500 PMCID: PMC9992055 DOI: 10.1016/j.bbrc.2023.02.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 01/30/2023] [Accepted: 02/07/2023] [Indexed: 02/11/2023]
Abstract
Obesity is a major risk factor for type 2 diabetes, coronary heart disease, and strok. These diseases are associated with profound alterations in gene expression in metabolic tissues. Epigenetic-mediated regulation of gene expression is one mechanism through which environmental factors, such as diet, modify gene expression and disease predisposition. However, epigenetic control of gene expression in obesity and insulin resistance is not fully characterized. We discovered that liver-specific stearoyl-CoA desaturase-1 (Scd1) knockout mice (LKO) fed a high-carbohydrate low-fat diet exhibit dramatic changes in hepatic gene expression and metabolites of the folate cycle and one-carbon metabolism respectively for the synthesis of S-adenosylmethionine (SAM). LKO mice show an increased ratio of S-adenosylmethionine to S-adenosylhomocysteine, a marker for increased cellular methylation capacity. Furthermore, expression of DNA and histone methyltransferase genes is up-regulated while the mRNA and protein levels of the non-DNA methyltransferases including phosphatidylethanolamine methyltransferase (PEMT), Betaine homocysteine methyltransferase (Bhmt), and the SAM-utilizing enzymes such as glycine-N-methyltransferase (Gnmt) and guanidinoacetate methyltransferase (Gamt) are generally down-regulated. Feeding LKO mice a high carbohydrate diet supplemented with triolein, but not tristearin, and increased endogenous hepatic synthesis of oleate but not palmitoleate in Scd1 global knockout mice normalized one carbon gene expression and metabolite levels. Additionally, changes in one carbon gene expression are independent of the PGC-1α-mediated ER stress response previously reported in the LKO mice. Together, these results highlight the important role of oleate in maintaining one-carbon cycle homeostasis and point to observed changes in one-carbon metabolism as a novel mediator of the Scd1 deficiency-induced liver phenotype.
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Affiliation(s)
- James M Ntambi
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA; Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, 53706, USA.
| | - Xueqing Liu
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Maggie S Burhans
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Ahmed ALjohani
- College of Science and Health Professions, King Saudi Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia
| | - Ebru Selin Selen
- Integrative Biology, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Mugagga Kalyesubula
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Fariba Assadi-Porter
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA; Integrative Biology, University of Wisconsin-Madison, Madison, WI, 53706, USA
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Kumar R, Kumar V, Arya R, Anand U, Priyadarshi RN. Association of COVID-19 with hepatic metabolic dysfunction. World J Virol 2022; 11:237-251. [PMID: 36188741 PMCID: PMC9523326 DOI: 10.5501/wjv.v11.i5.237] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 04/25/2022] [Accepted: 06/20/2022] [Indexed: 02/05/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic continues to be a global problem with over 438 million cases reported so far. Although it mostly affects the respiratory system, the involvement of extrapulmonary organs, including the liver, is not uncommon. Since the beginning of the pandemic, metabolic com-orbidities, such as obesity, diabetes, hypertension, and dyslipidemia, have been identified as poor prognostic indicators. Subsequent metabolic and lipidomic studies have identified several metabolic dysfunctions in patients with COVID-19. The metabolic alterations appear to be linked to the course of the disease and inflammatory reaction in the body. The liver is an important organ with high metabolic activity, and a significant proportion of COVID-19 patients have metabolic comorbidities; thus, this factor could play a key role in orchestrating systemic metabolic changes during infection. Evidence suggests that metabolic dysregulation in COVID-19 has both short- and long-term metabolic implications. Furthermore, COVID-19 has adverse associations with metabolic-associated fatty liver disease. Due to the ensuing effects on the renin-angiotensin-aldosterone system and ammonia metabolism, COVID-19 can have significant implications in patients with advanced chronic liver disease. A thorough understanding of COVID-19-associated metabolic dysfunction could lead to the identification of important plasma biomarkers and novel treatment targets. In this review, we discuss the current understanding of metabolic dysfunction in COVID-19, focusing on the liver and exploring the underlying mechanistic pathogenesis and clinical implications.
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Affiliation(s)
- Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna, Patna 801507, Bihar, India
| | - Vijay Kumar
- Department of Medicine, All India Institute of Medical Sciences, Patna, Patna 801507, Bihar, India
| | - Rahul Arya
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna, Patna 801507, Bihar, India
| | - Utpal Anand
- Department of Surgical Gastroenterology, All India Institute of Medical Sciences, Patna, Patna 801507, Bihar, India
| | - Rajeev Nayan Priyadarshi
- Department of Radiodiagnosis, All India Institute of Medical Sciences, Patna, Patna 801507, Bihar, India
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Zhang X, Liu T, Hou X, Hu C, Zhang L, Wang S, Zhang Q, Shi K. Multi-Channel Metabolomics Analysis Identifies Novel Metabolite Biomarkers for the Early Detection of Fatty Liver Disease in Dairy Cows. Cells 2022; 11:cells11182883. [PMID: 36139459 PMCID: PMC9496829 DOI: 10.3390/cells11182883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 09/09/2022] [Accepted: 09/10/2022] [Indexed: 11/17/2022] Open
Abstract
Fatty liver disease, a type of metabolic disorder, frequently occurs in dairy cows during the parturition period, causing a high culling rate and, therefore, considerable economic losses in the dairy industry owing to the lack of effective diagnostic methods. Here, metabolite biomarkers were identified and validated for the diagnosis of metabolic disorders. A total of 58 participant cows, including severe fatty liver disease and normal control groups, in the discovery set (liver biopsy tested, n = 18), test set (suspected, n = 20) and verification set (liver biopsy tested, n = 20), were strictly recruited and a sample collected for their feces, urine, and serum. Non-targeted GC-MS-based metabolomics methods were used to characterize the metabolite profiles and to screen in the discovery set. Eventually, ten novel biomarkers involved in bile acid, amino acid, and fatty acid were identified and validated in the test set. Each of them had a higher diagnostic ability than the traditional serum biochemical indicators, with an average area under the receiver operating characteristic curve of 0.830 ± 0.0439 (n = 10) versus 0.377 ± 0.182 (n = 9). Especially, combined biomarker panels via different metabolic pipelines had much better diagnostic sensitivity and specificity than every single biomarker, suggesting their powerful utilization potentiality for the early detection of fatty liver disease. Intriguingly, the serum biomarkers were confirmed perfectly in the verification set. Moreover, common biological pathways were found to be underlying the pathogenesis of fatty liver syndrome in cattle via different metabolic pipelines. These newly-discovered and non-invasive metabolic biomarkers are meaningful in reducing the high culling rate of cows and, therefore, benefit the sustainable development of the dairy industry.
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11
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Cao P, Chen Q, Shi C, Wang L, Gong Z. Fusobacterium nucleatum promotes the development of acute liver failure by inhibiting the NAD + salvage metabolic pathway. Gut Pathog 2022; 14:29. [PMID: 35765030 PMCID: PMC9238040 DOI: 10.1186/s13099-022-00503-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 06/01/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Acute liver failure (ALF) patients are often accompanied by severe energy metabolism abnormalities and intestinal microecological imbalance. The intestinal mucosal barrier is severely damaged. Intestinal endotoxin can induce intestinal endotoxemia through the "Gut-Liver axis". More and more evidence shows that members of the gut microbiota, especially Fusobacterium nucleatum (F. nucleatum), are related to inflammatory bowel disease, but whether F. nucleatum is involved in the development of ALF and whether it affects the liver energy metabolism is unclear. METHODS This study first detected the abundance of F. nucleatum and its effect on ALF disease, and explored whether F. nucleatum aggravated liver inflammation in vitro and in vivo. RESULTS Our data showed that liver tissues of ALF patients contained different abundances of F. nucleatum, which were related to the degree of liver inflammation. In addition, we found that F. nucleatum infection affected the energy metabolism of the liver during the development of ALF, inhibited the synthesis pathway of nicotinamide adenine dinucleotide (NAD+)'s salvage metabolism, and promoted inflammatory damage in the liver. In terms of mechanism, F. nucleatum inhibited NAD+ and the NAD+-dependent SIRT1/AMPK signaling pathway, and promoted liver damage of ALF. CONCLUSIONS Fusobacterium nucleatum coordinates a molecular network including NAD+ and SIRT1 to control the progress of ALF. Detection and targeting of F. nucleatum and its related pathways may provide valuable insights for the treatment of ALF.
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Affiliation(s)
- Pan Cao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, 238 Jie Fang Road, Wuhan, 430060, People's Republic of China
| | - Qian Chen
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, 238 Jie Fang Road, Wuhan, 430060, People's Republic of China
| | - Chunxia Shi
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, 238 Jie Fang Road, Wuhan, 430060, People's Republic of China
| | - Luwen Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, 238 Jie Fang Road, Wuhan, 430060, People's Republic of China
| | - Zuojiong Gong
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, 238 Jie Fang Road, Wuhan, 430060, People's Republic of China.
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12
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Mizuno R, Hojo H, Takahashi M, Kashio S, Enya S, Nakao M, Konishi R, Yoda M, Harata A, Hamanishi J, Kawamoto H, Mandai M, Suzuki Y, Miura M, Bamba T, Izumi Y, Kawaoka S. Remote solid cancers rewire hepatic nitrogen metabolism via host nicotinamide-N-methyltransferase. Nat Commun 2022; 13:3346. [PMID: 35705545 PMCID: PMC9200709 DOI: 10.1038/s41467-022-30926-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 05/20/2022] [Indexed: 12/14/2022] Open
Abstract
Cancers disrupt host homeostasis in various manners but the identity of host factors underlying such disruption remains largely unknown. Here we show that nicotinamide-N-methyltransferase (NNMT) is a host factor that mediates metabolic dysfunction in the livers of cancer-bearing mice. Multiple solid cancers distantly increase expression of Nnmt and its product 1-methylnicotinamide (MNAM) in the liver. Multi-omics analyses reveal suppression of the urea cycle accompanied by accumulation of amino acids, and enhancement of uracil biogenesis in the livers of cancer-bearing mice. Importantly, genetic deletion of Nnmt leads to alleviation of these metabolic abnormalities, and buffers cancer-dependent weight loss and reduction of the voluntary wheel-running activity. Our data also demonstrate that MNAM is capable of affecting urea cycle metabolites in the liver. These results suggest that cancers up-regulate the hepatic NNMT pathway to rewire liver metabolism towards uracil biogenesis rather than nitrogen disposal via the urea cycle, thereby disrupting host homeostasis. The presence of cancer can induce systemic disruption of the host homeostasis. Here, the authors show that different solid tumours remotely increase hepatic nicotinamide-Nmethyltransferase disrupting the host urea cycle metabolism in the liver.
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Affiliation(s)
- Rin Mizuno
- Inter-Organ Communication Research Team, Institute for Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan.,Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan
| | - Hiroaki Hojo
- Inter-Organ Communication Research Team, Institute for Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan.,The Thomas N. Sato BioMEC-X Laboratories, Advanced Telecommunications Research Institute International (ATR), Kyoto, 619-0237, Japan.,ERATO Sato Live Bio-forecasting Project, Japan Science and Technology Agency (JST), Kyoto, 619-0237, Japan
| | - Masatomo Takahashi
- Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan
| | - Soshiro Kashio
- Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Sora Enya
- The Thomas N. Sato BioMEC-X Laboratories, Advanced Telecommunications Research Institute International (ATR), Kyoto, 619-0237, Japan.,ERATO Sato Live Bio-forecasting Project, Japan Science and Technology Agency (JST), Kyoto, 619-0237, Japan
| | - Motonao Nakao
- Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan
| | - Riyo Konishi
- Inter-Organ Communication Research Team, Institute for Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan
| | - Mayuko Yoda
- Inter-Organ Communication Research Team, Institute for Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan
| | - Ayano Harata
- Inter-Organ Communication Research Team, Institute for Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan
| | - Junzo Hamanishi
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan
| | - Hiroshi Kawamoto
- Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan
| | - Masaki Mandai
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan
| | - Yutaka Suzuki
- Graduate School of Frontier Science, The University of Tokyo, Chiba, 277-8562, Japan
| | - Masayuki Miura
- Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Takeshi Bamba
- Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan
| | - Yoshihiro Izumi
- Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan
| | - Shinpei Kawaoka
- Inter-Organ Communication Research Team, Institute for Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan. .,The Thomas N. Sato BioMEC-X Laboratories, Advanced Telecommunications Research Institute International (ATR), Kyoto, 619-0237, Japan. .,ERATO Sato Live Bio-forecasting Project, Japan Science and Technology Agency (JST), Kyoto, 619-0237, Japan. .,Department of Integrative Bioanalytics, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, 980-8575, Japan.
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13
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Liu A, Guo M, He L, Martínez MA, Martínez M, Lopez-Torres B, Martínez-Larrañaga MR, Wang X, Anadón A, Ares I. Nicotinamide N-methyltransferase protects against deoxynivalenol-induced growth inhibition by suppressing pro-inflammatory cytokine expression. Food Chem Toxicol 2022; 163:112969. [PMID: 35351591 DOI: 10.1016/j.fct.2022.112969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/22/2022] [Accepted: 03/24/2022] [Indexed: 11/19/2022]
Abstract
Deoxynivalenol (DON) is an inevitable contaminant in cereals for infants. Indeed, children's growth retardation caused by widespread DON pollution has become a global problem that cannot be ignored. Accumulating evidence has shown that DON stunts growth in children through pro-inflammatory cytokines. An exogenous increase of methylnicotinamide, a metabolite produced by nicotinamide N-methyltransferase (NNMT), has anti-inflammatory effects, but it is not clear whether NNMT has the same effect, and the role of NNMT in DON-induced inflammation and growth impairment remains indistinct. The present research reports that NNMT is an inflammatory self-protective factor in DON-exposed L02 cells. DON promoted the production of pro-inflammatory cytokines. Furthermore, DON increased NNMT to reduce pro-inflammatory cytokines, including interleukin (IL)-1β, IL-11 and IL-6, and thus increased IGF-1 and cell viability, alleviating the cell growth inhibition induced by DON. Interestingly, NNMT negatively regulated the expression of IL-1β through Sirtuin type 1 (SIRT1). Collectively, these findings provide new mechanistic insights into the toxicity of DON-induced growth retardation and inflammatory responses in children.
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Affiliation(s)
- Aimei Liu
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei, 430070, China; Hanxi Key Lab. for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, 030801, Shanxi, China
| | - Mingyue Guo
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
| | - Lixuan He
- MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Hubei, 430070, China
| | - María-Aránzazu Martínez
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, Madrid, 28040, Spain
| | - Marta Martínez
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, Madrid, 28040, Spain
| | - Bernardo Lopez-Torres
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, Madrid, 28040, Spain
| | - María-Rosa Martínez-Larrañaga
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, Madrid, 28040, Spain
| | - Xu Wang
- National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei, 430070, China; MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Hubei, 430070, China.
| | - Arturo Anadón
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, Madrid, 28040, Spain.
| | - Irma Ares
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, Madrid, 28040, Spain
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14
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Yang H, Mayneris-Perxachs J, Boqué N, del Bas JM, Arola L, Yuan M, Türkez H, Uhlén M, Borén J, Zhang C, Mardinoglu A, Caimari A. Combined Metabolic Activators Decrease Liver Steatosis by Activating Mitochondrial Metabolism in Hamsters Fed with a High-Fat Diet. Biomedicines 2021; 9:1440. [PMID: 34680557 PMCID: PMC8533474 DOI: 10.3390/biomedicines9101440] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/04/2021] [Accepted: 10/06/2021] [Indexed: 01/13/2023] Open
Abstract
Although the prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase, there is no effective treatment approved for this condition. We previously showed, in high-fat diet (HFD)-fed mice, that the supplementation of combined metabolic activators (CMA), including nicotinamide riboside (NAD+ precursor) and the potent glutathione precursors serine and N-acetyl-l-cysteine (NAC), significantly decreased fatty liver by promoting fat oxidation in mitochondria. Afterwards, in a one-day proof-of-concept human supplementation study, we observed that this CMA, including also L-carnitine tartrate (LCT), resulted in increased fatty acid oxidation and de novo glutathione synthesis. However, the underlying molecular mechanisms associated with supplementation of CMA have not been fully elucidated. Here, we demonstrated in hamsters that the chronic supplementation of this CMA (changing serine for betaine) at two doses significantly decreased hepatic steatosis. We further generated liver transcriptomics data and integrated these data using a liver-specific genome-scale metabolic model of liver tissue. We systemically determined the molecular changes after the supplementation of CMA and found that it activates mitochondria in the liver tissue by modulating global lipid, amino acid, antioxidant and folate metabolism. Our findings provide extra evidence about the beneficial effects of a treatment based on this CMA against NAFLD.
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Affiliation(s)
- Hong Yang
- Science for Life Laboratory, KTH Royal Institute of Technology, SE-17165 Stockholm, Sweden; (H.Y.); (M.Y.); (M.U.); (C.Z.)
| | - Jordi Mayneris-Perxachs
- Department of Diabetes, Endocrinology and Nutrition, Girona Biomedical Research Institute (IDIBGI), Hospital Universitari de Girona Doctor Josep Trueta, 17190 Girona, Spain;
- Center for Pathophysiology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Noemí Boqué
- Eurecat, Centre Tecnològic de Catalunya, Technological Unit of Nutrition and Health, 43204 Reus, Spain; (N.B.); (J.M.d.B.); (L.A.)
| | - Josep M. del Bas
- Eurecat, Centre Tecnològic de Catalunya, Technological Unit of Nutrition and Health, 43204 Reus, Spain; (N.B.); (J.M.d.B.); (L.A.)
| | - Lluís Arola
- Eurecat, Centre Tecnològic de Catalunya, Technological Unit of Nutrition and Health, 43204 Reus, Spain; (N.B.); (J.M.d.B.); (L.A.)
- Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Campus Sescelades, Universitat Rovira i Virgili, 43007 Tarragona, Spain
| | - Meng Yuan
- Science for Life Laboratory, KTH Royal Institute of Technology, SE-17165 Stockholm, Sweden; (H.Y.); (M.Y.); (M.U.); (C.Z.)
| | - Hasan Türkez
- Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum 25030, Turkey;
| | - Mathias Uhlén
- Science for Life Laboratory, KTH Royal Institute of Technology, SE-17165 Stockholm, Sweden; (H.Y.); (M.Y.); (M.U.); (C.Z.)
| | - Jan Borén
- Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital, SE-40233 Gothenburg, Sweden;
| | - Cheng Zhang
- Science for Life Laboratory, KTH Royal Institute of Technology, SE-17165 Stockholm, Sweden; (H.Y.); (M.Y.); (M.U.); (C.Z.)
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH Royal Institute of Technology, SE-17165 Stockholm, Sweden; (H.Y.); (M.Y.); (M.U.); (C.Z.)
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London WC2R 2LS, UK
| | - Antoni Caimari
- Eurecat, Centre Tecnològic de Catalunya, Technological Unit of Nutrition and Health, 43204 Reus, Spain; (N.B.); (J.M.d.B.); (L.A.)
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15
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Quesada-Vázquez S, Colom-Pellicer M, Navarro-Masip È, Aragonès G, Del Bas JM, Caimari A, Escoté X. Supplementation with a Specific Combination of Metabolic Cofactors Ameliorates Non-Alcoholic Fatty Liver Disease, Hepatic Fibrosis, and Insulin Resistance in Mice. Nutrients 2021; 13:3532. [PMID: 34684533 PMCID: PMC8541294 DOI: 10.3390/nu13103532] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/29/2021] [Accepted: 09/30/2021] [Indexed: 11/21/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have emerged as the leading causes of chronic liver disease in the world. Obesity, insulin resistance, and dyslipidemia are multifactorial risk factors strongly associated with NAFLD/NASH. Here, a specific combination of metabolic cofactors (a multi-ingredient; MI) containing precursors of glutathione (GSH) and nicotinamide adenine dinucleotide (NAD+) (betaine, N-acetyl-cysteine, L-carnitine and nicotinamide riboside) was evaluated as effective treatment for the NAFLD/NASH pathophysiology. Six-week-old male mice were randomly divided into control diet animals and animals exposed to a high fat and high fructose/sucrose diet to induce NAFLD. After 16 weeks, diet-induced NAFLD mice were distributed into two groups, treated with the vehicle (HFHFr group) or with a combination of metabolic cofactors (MI group) for 4 additional weeks, and blood and liver were obtained from all animals for biochemical, histological, and molecular analysis. The MI treatment reduced liver steatosis, decreasing liver weight and hepatic lipid content, and liver injury, as evidenced by a pronounced decrease in serum levels of liver transaminases. Moreover, animals supplemented with the MI cocktail showed a reduction in the gene expression of some proinflammatory cytokines when compared with their HFHFr counterparts. In addition, MI supplementation was effective in decreasing hepatic fibrosis and improving insulin sensitivity, as observed by histological analysis, as well as a reduction in fibrotic gene expression (Col1α1) and improved Akt activation, respectively. Taken together, supplementation with this specific combination of metabolic cofactors ameliorates several features of NAFLD, highlighting this treatment as a potential efficient therapy against this disease in humans.
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Affiliation(s)
- Sergio Quesada-Vázquez
- Eurecat, Technology Centre of Catalunya, Nutrition and Health Unit, 43204 Reus, Spain; (S.Q.-V.); (J.M.D.B.)
| | - Marina Colom-Pellicer
- Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, 43007 Tarragona, Spain; (M.C.-P.); (È.N.-M.); (G.A.)
| | - Èlia Navarro-Masip
- Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, 43007 Tarragona, Spain; (M.C.-P.); (È.N.-M.); (G.A.)
| | - Gerard Aragonès
- Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, 43007 Tarragona, Spain; (M.C.-P.); (È.N.-M.); (G.A.)
| | - Josep M. Del Bas
- Eurecat, Technology Centre of Catalunya, Nutrition and Health Unit, 43204 Reus, Spain; (S.Q.-V.); (J.M.D.B.)
| | - Antoni Caimari
- Eurecat, Centre Tecnològic de Catalunya, Biotechnology Area, 43204 Reus, Spain;
| | - Xavier Escoté
- Eurecat, Technology Centre of Catalunya, Nutrition and Health Unit, 43204 Reus, Spain; (S.Q.-V.); (J.M.D.B.)
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16
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Eudy BJ, McDermott CE, Liu X, da Silva RP. Targeted and untargeted metabolomics provide insight into the consequences of glycine-N-methyltransferase deficiency including the novel finding of defective immune function. Physiol Rep 2021; 8:e14576. [PMID: 32951289 PMCID: PMC7507444 DOI: 10.14814/phy2.14576] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 08/25/2020] [Accepted: 08/25/2020] [Indexed: 01/27/2023] Open
Abstract
Fatty liver disease is increasing along with the prevalence of obesity and type‐2 diabetes. Hepatic fibrosis is a major health complication for which there are no efficacious treatment options available. A better understanding of the fundamental mechanisms that contribute to the accumulation of fibrosis is needed. Glycine‐N‐methyltransferase (GNMT) is a critical enzyme in one‐carbon metabolism that serves to regulate methylation and remethylation reactions. GNMT knockout (GNMT‐/‐) mice display spontaneous hepatic fibrosis and later develop hepatocellular carcinoma. Previous literature supports the idea that hypermethylation as a consequence of GNMT deletion contributes to the hepatic phenotype observed. However, limited metabolomic information is available and the underlying mechanisms that contribute to hepatic fibrogenesis in GNMT‐/‐ mice are still incomplete. Therefore, our goals were to use dietary intervention to determine whether increased lipid load exacerbates steatosis and hepatic fibrosis in this model and to employ both targeted and untargeted metabolomics to further understand the metabolic consequences of GNMT deletion. We find that GNMT mice fed high‐fat diet do not accumulate more lipid or fibrosis in the liver and are in fact resistant to weight gain. Metabolomics analysis confirmed that pan‐hypermethylation occurs in GNMT mice resulting in a depletion of nicotinamide intermediate metabolites. Further, there is a disruption in tryptophan catabolism that prevents adequate immune cell activation in the liver. The chronic cellular damage cannot be appropriately cleared due to a lack of immune checkpoint activation. This mouse model is an excellent example of how a disruption in small molecule metabolism can significantly impact immune function.
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Affiliation(s)
- Brandon J Eudy
- Department of Food Science and Human Nutrition, University of Florida, Gainesville, FL, USA
| | - Caitlin E McDermott
- Department of Food Science and Human Nutrition, University of Florida, Gainesville, FL, USA
| | - Xiuli Liu
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA
| | - Robin P da Silva
- Department of Food Science and Human Nutrition, University of Florida, Gainesville, FL, USA
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17
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Hammoudeh SM, Hammoudeh AM, Bhamidimarri PM, Mahboub B, Halwani R, Hamid Q, Rahmani M, Hamoudi R. Insight into molecular mechanisms underlying hepatic dysfunction in severe COVID-19 patients using systems biology. World J Gastroenterol 2021; 27:2850-2870. [PMID: 34135558 PMCID: PMC8173390 DOI: 10.3748/wjg.v27.i21.2850] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/30/2021] [Accepted: 05/10/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The coronavirus disease 2019 (COVID-19), a pandemic contributing to more than 105 million cases and more than 2.3 million deaths worldwide, was described to be frequently accompanied by extrapulmonary manifestations, including liver dysfunction. Liver dysfunction and elevated liver enzymes were observed in about 53% of COVID-19 patients.
AIM To gain insight into transcriptional abnormalities in liver tissue of severe COVID-19 patients that may result in liver dysfunction.
METHODS The transcriptome of liver autopsy samples from severe COVID-19 patients against those of non-COVID donors was analyzed. Differentially expressed genes were identified from normalized RNA-seq data and analyzed for the enrichment of functional clusters and pathways. The differentially expressed genes were then compared against the genetic signatures of liver diseases including cirrhosis, fibrosis, non-alcoholic fatty liver disease (NAFLD), and hepatitis A/B/C. Gene expression of some differentially expressed genes was assessed in the blood samples of severe COVID-19 patients with liver dysfunction using qRT-PCR.
RESULTS Analysis of the differential transcriptome of the liver tissue of severe COVID-19 patients revealed a significant upregulation of transcripts implicated in tissue remodeling including G-coupled protein receptors family genes, DNAJB1, IGF2, EGFR, and HDGF. Concordantly, the differential transcriptome of severe COVID-19 liver tissues substantially overlapped with the disease signature of liver diseases characterized with pathological tissue remodeling (liver cirrhosis, Fibrosis, NAFLD, and hepatitis A/B/C). Moreover, we observed a significant suppression of transcripts implicated in metabolic pathways as well as mitochondrial function, including cytochrome P450 family members, ACAD11, CIDEB, GNMT, and GPAM. Consequently, drug and xenobiotics metabolism pathways are significantly suppressed suggesting a decrease in liver detoxification capacity. In correspondence with the RNA-seq data analysis, we observed a significant upregulation of DNAJB1 and HSP90AB1 as well as significant downregulation of CYP39A1 in the blood plasma of severe COVID-19 patients with liver dysfunction.
CONCLUSION Severe COVID-19 patients appear to experience significant transcriptional shift that may ensue tissue remodeling, mitochondrial dysfunction and lower hepatic detoxification resulting in the clinically observed liver dysfunction.
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Affiliation(s)
- Sarah Musa Hammoudeh
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Arabella Musa Hammoudeh
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- General Surgery Department, Tawam Hospital, SEHA, Al-Ain 15258, United Arab Emirates
| | - Poorna Manasa Bhamidimarri
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Bassam Mahboub
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- Rashid Hospital, 315 Umm Hurair Second, Dubai Health Authority, Dubai 4545, United Arab Emirates
| | - Rabih Halwani
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Qutayba Hamid
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- Meakins-Christie Laboratories, McGill University, Quebec H4A 3J1, Montreal, Canada
| | - Mohamed Rahmani
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Rifat Hamoudi
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- Division of Surgery and Interventional Science, University College London, London W1W 7TY, United Kingdom
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18
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Yang D, Zhang X, Yue L, Hu H, Wei X, Guo Q, Zhang B, Fan X, Xin Y, Oh Y, Gu N. Thiamethoxam induces nonalcoholic fatty liver disease in mice via methionine metabolism disturb via nicotinamide N-methyltransferase overexpression. CHEMOSPHERE 2021; 273:129727. [PMID: 33524747 DOI: 10.1016/j.chemosphere.2021.129727] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 01/10/2021] [Accepted: 01/19/2021] [Indexed: 06/12/2023]
Abstract
Thiamethoxam (TMX) is one of the major compounds of neonicotinoids, the most widely used class of insecticides worldwide. Previously, TMX was considered a non-toxic neonicotinoid insecticide to mammals. However, the genotoxicity, cytotoxicity, and hepatotoxicity of TMX in mammals were recently reported. Thus far, the effects of TMX on the mouse liver and its detailed mechanism remain unclear. NNMT, strongly expressed in the liver, plays a critical role in body energy expenditure. To confirm the potential pathogenesis of liver dysfunction induced by TMX, ICR mice were exposed to TMX at a dose of 4 mg/kg and 20 mg/kg by gavage administration for 12 weeks. The data showed that chronic TMX exposure caused dyslipidemia and nonalcoholic fatty liver disease (NAFLD) in mice. Moreover, aggravated oxidative stress, dysfunction, and disorganized structure were also observed in TMX-treated mouse livers. In addition, increases of PPARγ, fatty acid synthase, and NNMT expression, as well as decreases of PPARα and GNMT expression, S-adenosylmethionine deficiency, and methionine metabolism disorder were also observed in TMX-treated mouse livers. These results suggest that chronic TMX exposure induces dyslipidemia and NAFLD in mice. Moreover, inhibition of NNMT in hepatocytes significantly reversed the effects of TMX. The molecular mechanism of TMX-induced NAFLD is mostly through NNMT-mediated methionine metabolism and methyl donor balance, which ultimately regulates PPARα signaling pathway. Inhibition of NNMT could be a potentially novel strategy for blocking the progression of NAFLD induced by TMX.
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Affiliation(s)
- Daqian Yang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Xiaoting Zhang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Lei Yue
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Hailong Hu
- Department of Medicine, Renal Electrolyte and Hypertension Division, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Xiangjuan Wei
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Qian Guo
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, USA
| | - Boya Zhang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Xingpei Fan
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Yuan Xin
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Yuri Oh
- Faculty of Education, Wakayama University, Wakayama, Japan
| | - Ning Gu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China; State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China.
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19
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Padmanabhan N, Kyon HK, Boot A, Lim K, Srivastava S, Chen S, Wu Z, Lee HO, Mukundan VT, Chan C, Chan YK, Xuewen O, Pitt JJ, Isa ZFA, Xing M, Lee MH, Tan ALK, Ting SHW, Luftig MA, Kappei D, Kruger WD, Bian J, Ho YS, Teh M, Rozen SG, Tan P. Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation. Genome Biol 2021; 22:167. [PMID: 34074348 PMCID: PMC8170989 DOI: 10.1186/s13059-021-02375-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 05/06/2021] [Indexed: 02/06/2023] Open
Abstract
Background CIMP (CpG island methylator phenotype) is an epigenetic molecular subtype, observed in multiple malignancies and associated with the epigenetic silencing of tumor suppressors. Currently, for most cancers including gastric cancer (GC), mechanisms underlying CIMP remain poorly understood. We sought to discover molecular contributors to CIMP in GC, by performing global DNA methylation, gene expression, and proteomics profiling across 14 gastric cell lines, followed by similar integrative analysis in 50 GC cell lines and 467 primary GCs. Results We identify the cystathionine beta-synthase enzyme (CBS) as a highly recurrent target of epigenetic silencing in CIMP GC. Likewise, we show that CBS epimutations are significantly associated with CIMP in various other cancers, occurring even in premalignant gastroesophageal conditions and longitudinally linked to clinical persistence. Of note, CRISPR deletion of CBS in normal gastric epithelial cells induces widespread DNA methylation changes that overlap with primary GC CIMP patterns. Reflecting its metabolic role as a gatekeeper interlinking the methionine and homocysteine cycles, CBS loss in vitro also causes reductions in the anti-inflammatory gasotransmitter hydrogen sulfide (H2S), with concomitant increase in NF-κB activity. In a murine genetic model of CBS deficiency, preliminary data indicate upregulated immune-mediated transcriptional signatures in the stomach. Conclusions Our results implicate CBS as a bi-faceted modifier of aberrant DNA methylation and inflammation in GC and highlights H2S donors as a potential new therapy for CBS-silenced lesions. Supplementary Information The online version contains supplementary material available at 10.1186/s13059-021-02375-2.
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Affiliation(s)
- Nisha Padmanabhan
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore
| | - Huang Kie Kyon
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore
| | - Arnoud Boot
- Centre for Computational Biology, Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Kevin Lim
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore
| | - Supriya Srivastava
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Shuwen Chen
- Bioprocessing Technology Institute, A*STAR, 20 Biopolis Way, #06-01 Centros, Singapore, 138668, Singapore
| | - Zhiyuan Wu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Hyung-Ok Lee
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Vineeth T Mukundan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
| | - Charlene Chan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
| | - Yarn Kit Chan
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore
| | - Ong Xuewen
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore
| | - Jason J Pitt
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
| | - Zul Fazreen Adam Isa
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore
| | - Manjie Xing
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore
| | - Ming Hui Lee
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore
| | - Angie Lay Keng Tan
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore
| | - Shamaine Ho Wei Ting
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore
| | - Micah A Luftig
- Department of Molecular Genetics and Microbiology, Duke Centre for Virology, Duke University School of Medicine, Durham, NC, USA
| | - Dennis Kappei
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117596, Singapore
| | - Warren D Kruger
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Jinsong Bian
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.,National University of Singapore (Suzhou) Research Institute, Suzhou, 215123, China
| | - Ying Swan Ho
- Bioprocessing Technology Institute, A*STAR, 20 Biopolis Way, #06-01 Centros, Singapore, 138668, Singapore
| | - Ming Teh
- Department of Pathology, National University of Singapore, Singapore, 119228, Singapore
| | - Steve George Rozen
- Centre for Computational Biology, Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Patrick Tan
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore. .,Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. .,Genome Institute of Singapore, Singapore, 138672, Singapore. .,SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore, 169856, Singapore. .,Singapore Gastric Cancer Consortium, Singapore, 119074, Singapore. .,Department of Physiology, National University of Singapore, Singapore, 117593, Singapore.
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20
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Zhou L, Shi DP, Chu WJ, Song S, Hao XH, Yang LL, Xu HF. Nicotinamide suppresses bevacizumab-induced epithelial-mesenchymal transition of ARPE-19 cells by attenuating oxidative stress. Int J Ophthalmol 2021; 14:481-488. [PMID: 33875936 DOI: 10.18240/ijo.2021.04.01] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 10/12/2020] [Indexed: 11/23/2022] Open
Abstract
AIM To investigate the effects of nicotinamide (NAM) on bevacizumab (BEV)-induced epithelial-mesenchymal transition (EMT) of human retinal pigment epithelial cells (ARPE-19) and the underling mechanisms. METHODS ARPE-19 cells were treated with BEV for 24, 48, and 72h, and the variation degrees of EMT-related markers (fibronectin, α-SMA, vimentin, and ZO-1) were assessed by Western blotting to select the optimal treatment time point which exhibited the most obvious changes of EMT-related markers for the subsequent experiments. Furthermore, NAM was added to the medium, the mRNA and protein levels of the EMT-related markers were then measured. The accumulation of reactive oxygen species (ROS) and H2O2 and the total antioxidant capacity (TAC) of the cells were also measured to evaluate the level of oxidative stress. RESULTS After being treated with BEV for 72h, the protein expression levels of EMT-related markers in ARPE-19 cells showed significant changes. Meanwhile the levels of ROS and H2O2 were obviously increased, and the TAC of ARPE-19 cells was decreased. Totally 72h was chosen to be the optimal treatment time point in subsequent experiments. Furthermore, NAM inhibited BEV-induced EMT by downregulating fibronectin, α-SMA, and vimentin and upregulating ZO-1, decreased the accumulation of ROS and H2O2, and enhanced TAC in BEV-treated ARPE-19 cells. CONCLUSION This study demonstrates that NAM suppressed BEV-induced EMT in ARPE-19 cells by attenuating oxidative stress. Hence, NAM may be a potential therapeutic agent for alleviating neovascular fibrosis of the ocular fundus after anti-vascular endothelial growth factor therapy.
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Affiliation(s)
- Li Zhou
- Medical College, Qingdao University, Qingdao 266071, Shandong Province, China.,State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao 266071, Shandong Province, China
| | - De-Peng Shi
- Qingdao Eye Hospital, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao 266071, Shandong Province, China
| | - Wen-Juan Chu
- Qingdao Eye Hospital, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao 266071, Shandong Province, China
| | - Shan Song
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao 266071, Shandong Province, China
| | - Xiang-Hui Hao
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao 266071, Shandong Province, China
| | - Ling-Ling Yang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao 266071, Shandong Province, China
| | - Hai-Feng Xu
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao 266071, Shandong Province, China.,Qingdao Eye Hospital, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao 266071, Shandong Province, China
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21
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Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma. Nat Commun 2021; 12:1455. [PMID: 33674593 PMCID: PMC7935900 DOI: 10.1038/s41467-021-21804-1] [Citation(s) in RCA: 129] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 02/12/2021] [Indexed: 12/17/2022] Open
Abstract
T-cell exhaustion denotes a hypofunctional state of T lymphocytes commonly found in cancer, but how tumor cells drive T-cell exhaustion remains elusive. Here, we find T-cell exhaustion linked to overall survival in 675 hepatocellular carcinoma (HCC) patients with diverse ethnicities and etiologies. Integrative omics analyses uncover oncogenic reprograming of HCC methionine recycling with elevated 5-methylthioadenosine (MTA) and S-adenosylmethionine (SAM) to be tightly linked to T-cell exhaustion. SAM and MTA induce T-cell dysfunction in vitro. Moreover, CRISPR-Cas9-mediated deletion of MAT2A, a key SAM producing enzyme, results in an inhibition of T-cell dysfunction and HCC growth in mice. Thus, reprogramming of tumor methionine metabolism may be a viable therapeutic strategy to improve HCC immunity. Intratumoral CD8+ T cells commonly display a dysfunctional state, however it remains unclear whether tumor cell metabolism actively promotes T-cell exhaustion. Here, the authors show that the tumor methionine recycling pathway has a central role in promoting T-cell dysfunction in hepatocellular carcinoma, contributing to tumor immune evasion.
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22
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Abstract
T-cell exhaustion denotes a hypofunctional state of T lymphocytes commonly found in cancer, but how tumor cells drive T-cell exhaustion remains elusive. Here, we find T-cell exhaustion linked to overall survival in 675 hepatocellular carcinoma (HCC) patients with diverse ethnicities and etiologies. Integrative omics analyses uncover oncogenic reprograming of HCC methionine recycling with elevated 5-methylthioadenosine (MTA) and S-adenosylmethionine (SAM) to be tightly linked to T-cell exhaustion. SAM and MTA induce T-cell dysfunction in vitro. Moreover, CRISPR-Cas9-mediated deletion of MAT2A, a key SAM producing enzyme, results in an inhibition of T-cell dysfunction and HCC growth in mice. Thus, reprogramming of tumor methionine metabolism may be a viable therapeutic strategy to improve HCC immunity.
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23
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Sun M, Zhang J, Liang S, Du Z, Liu J, Sun Z, Duan J. Metabolomic characteristics of hepatotoxicity in rats induced by silica nanoparticles. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 208:111496. [PMID: 33099137 DOI: 10.1016/j.ecoenv.2020.111496] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 10/09/2020] [Accepted: 10/10/2020] [Indexed: 06/11/2023]
Abstract
Silica nanoparticles (SiNPs) have become one of the most widely studied nanoparticles in nanotechnology for environmental health and safety. Although many studies have devoted to evaluating the hepatotoxicity of SiNPs, it is currently impossible to predict the extent of liver lipid metabolism disorder by identifying changes in metabolites. In the present study, 40 male Sprague-Dawley (SD) rats were randomly divided into control group and 3 groups with different doses (1.8 mg/kg body weight (bw), 5.4 mg/kg bw, 16.2 mg/kg bw), receiving intratracheal instillation of SiNPs. Liver tissue was taken for lipid level analysis, and serum was used for blood biochemical analysis. Then, the metabolites changes of liver tissue in rats were systematically analyzed using 1H nuclear magnetic resonance (1H NMR) techniques in combination with multivariate statistical analysis. SiNPs induced serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglyceride (TG) elevation in treated groups; TG and low-density lipoprotein cholesterol (LDL-C) were significantly higher in SiNPs-treated groups of high-dose, however high-density lipoprotein cholesterol (HDL-C) showed a declining trend in liver tissue. The orthogonal partial least squares discriminant analysis (OPLS-DA) scores plots revealed different metabolic profiles between control and high-dose group (Q2 =0.495, R2Y=0.802, p = 0.037), and a total of 11 differential metabolites. Pathway analysis indicated that SiNPs treatment mainly affected 10 metabolic pathways including purine metabolism, glucose-alanine cycle and metabolism of various amino acids such as glutamate, cysteine and aspartate (impact value>0.1, false discovery rate (FDR)< 0.05). The result indicated that exposure to SiNPs caused liver lipid metabolism disorder in rats, the biochemical criterions related to lipid metabolism changed significantly. The obviously changed metabolomics in SiNPs-treated rats mostly occurred in amino acids, organic acids and nucleosides.
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Affiliation(s)
- Mengqi Sun
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China
| | - Jingyi Zhang
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China
| | - Shuang Liang
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China
| | - Zhou Du
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China
| | - Jiangyan Liu
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China
| | - Zhiwei Sun
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China
| | - Junchao Duan
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China.
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24
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Kožich V, Majtan T. Inherited disorders of sulfur amino acid metabolism: recent advances in therapy. Curr Opin Clin Nutr Metab Care 2021; 24:62-70. [PMID: 33060459 DOI: 10.1097/mco.0000000000000705] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
PURPOSE OF REVIEW Metabolism of sulfur amino acids (SAA) provides compounds important for many cellular functions. Inherited disorders of SAA metabolism are typically severe multisystemic diseases affecting brain, liver, connective tissue, or vasculature. The review summarizes the present therapeutic approaches and advances in identifying novel treatment targets, and provides an overview of new therapies. RECENT FINDINGS Current treatments of genetic disorders of SAA metabolism are primarily based on modulation of affected pathways by dietary measures and provision of lacking products or scavenging of toxic molecules. Recent studies identified additional therapeutic targets distant from the primary defects and explored ideas envisioning novel treatments, such as chaperone and gene therapy. Recombinant protein production and engineering resulted in development and clinical testing of enzyme therapies for cystathionine β-synthase deficiency, the most common inborn error of SAA metabolism. SUMMARY Complex regulation of pathways involved in SAA metabolism and cellular consequences of genetic defects in SAA metabolism are only partially understood. There is a pressing need to increase substantially our knowledge of the disease mechanisms to develop more effective therapies for patients suffering from these rare disorders.
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Affiliation(s)
- Viktor Kožich
- Department of Pediatrics and Inherited Metabolic Disorders, Charles University-First Faculty of Medicine and General University Hospital, Czech Republic
| | - Tomas Majtan
- Section of Genetics and Metabolism, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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25
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Robinson AE, Binek A, Venkatraman V, Searle BC, Holewinski RJ, Rosenberger G, Parker SJ, Basisty N, Xie X, Lund PJ, Saxena G, Mato JM, Garcia BA, Schilling B, Lu SC, Van Eyk JE. Lysine and Arginine Protein Post-translational Modifications by Enhanced DIA Libraries: Quantification in Murine Liver Disease. J Proteome Res 2020; 19:4163-4178. [PMID: 32966080 DOI: 10.1021/acs.jproteome.0c00685] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Proteoforms containing post-translational modifications (PTMs) represent a degree of functional diversity only harnessed through analytically precise simultaneous quantification of multiple PTMs. Here we present a method to accurately differentiate an unmodified peptide from its PTM-containing counterpart through data-independent acquisition-mass spectrometry, leveraging small precursor mass windows to physically separate modified peptidoforms from each other during MS2 acquisition. We utilize a lysine and arginine PTM-enriched peptide assay library and site localization algorithm to simultaneously localize and quantify seven PTMs including mono-, di-, and trimethylation, acetylation, and succinylation in addition to total protein quantification in a single MS run without the need to enrich experimental samples. To evaluate biological relevance, this method was applied to liver lysate from differentially methylated nonalcoholic steatohepatitis (NASH) mouse models. We report that altered methylation and acetylation together with total protein changes drive the novel hypothesis of a regulatory function of PTMs in protein synthesis and mRNA stability in NASH.
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Affiliation(s)
- Aaron E Robinson
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California 90048, United States
| | - Aleksandra Binek
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California 90048, United States
| | - Vidya Venkatraman
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California 90048, United States
| | - Brian C Searle
- Department of Genome Sciences, University of Washington, Seattle, Washington 98195, United States
| | - Ronald J Holewinski
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California 90048, United States
| | - George Rosenberger
- Department of Systems Biology, Columbia University, New York, New York 10027, United States
| | - Sarah J Parker
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California 90048, United States
| | - Nathan Basisty
- Buck Institute for Research on Aging, Novato, California 94945, United States
| | - Xueshu Xie
- Buck Institute for Research on Aging, Novato, California 94945, United States
| | - Peder J Lund
- Department of Biochemistry and Biophysics, Epigenetics Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, United States
| | | | - José M Mato
- CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain
| | - Benjamin A Garcia
- Department of Biochemistry and Biophysics, Epigenetics Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, United States
| | - Birgit Schilling
- Buck Institute for Research on Aging, Novato, California 94945, United States
| | - Shelly C Lu
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, California 90048, United States
| | - Jennifer E Van Eyk
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California 90048, United States
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26
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Sundararaman N, Go J, Robinson AE, Mato JM, Lu SC, Van Eyk JE, Venkatraman V. PINE: An Automation Tool to Extract and Visualize Protein-Centric Functional Networks. JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY 2020; 31:1410-1421. [PMID: 32463229 PMCID: PMC10362945 DOI: 10.1021/jasms.0c00032] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Recent surges in mass spectrometry-based proteomics studies demand a concurrent rise in speedy and optimized data processing tools and pipelines. Although several stand-alone bioinformatics tools exist that provide protein-protein interaction (PPI) data, we developed Protein Interaction Network Extractor (PINE) as a fully automated, user-friendly, graphical user interface application for visualization and exploration of global proteome and post-translational modification (PTM) based networks. PINE also supports overlaying differential expression, statistical significance thresholds, and PTM sites on functionally enriched visualization networks to gain insights into proteome-wide regulatory mechanisms and PTM-mediated networks. To illustrate the relevance of the tool, we explore the total proteome and its PTM-associated relationships in two different nonalcoholic steatohepatitis (NASH) mouse models to demonstrate different context-specific case studies. The strength of this tool relies in its ability to (1) perform accurate protein identifier mapping to resolve ambiguity, (2) retrieve interaction data from multiple publicly available PPI databases, and (3) assimilate these complex networks into functionally enriched pathways, ontology categories, and terms. Ultimately, PINE can be used as an extremely powerful tool for novel hypothesis generation to understand underlying disease mechanisms.
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Affiliation(s)
- Niveda Sundararaman
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California 90048, United States
| | - James Go
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California 90048, United States
| | - Aaron E Robinson
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California 90048, United States
| | - José M Mato
- CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain
| | - Shelly C Lu
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, California 90048, United States
| | - Jennifer E Van Eyk
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California 90048, United States
| | - Vidya Venkatraman
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California 90048, United States
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27
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da Silva RP, Eudy BJ, Deminice R. One-Carbon Metabolism in Fatty Liver Disease and Fibrosis: One-Carbon to Rule Them All. J Nutr 2020; 150:994-1003. [PMID: 32119738 DOI: 10.1093/jn/nxaa032] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/14/2019] [Accepted: 01/30/2020] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a term used to characterize a range of disease states that involve the accumulation of fat in the liver but are not associated with excessive alcohol consumption. NAFLD is a prevalent disease that can progress to organ damage like liver cirrhosis and hepatocellular carcinoma. Many animal models have demonstrated that one-carbon metabolism is strongly associated with NAFLD. Phosphatidylcholine is an important phospholipid that affects hepatic lipid homeostasis and de novo synthesis of this phospholipid is associated with NAFLD. However, one-carbon metabolism serves to support all cellular methylation reactions and catabolism of methionine, serine, glycine, choline, betaine, tryptophan, and histidine. Several different pathways within one-carbon metabolism that play important roles in regulating energy metabolism and immune function have received less attention in the study of fatty liver disease and fibrosis. This review examines what we have learned about hepatic lipid metabolism and liver damage from the study of one-carbon metabolism thus far and highlights unexplored opportunities for future research.
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Affiliation(s)
- Robin P da Silva
- Department of Food Science and Human Nutrition, University of Florida, Gainesville, FL, USA
| | - Brandon J Eudy
- Department of Food Science and Human Nutrition, University of Florida, Gainesville, FL, USA
| | - Rafael Deminice
- Department of Physical Education, State University of Londrina, Londrina, Paraná, Brazil
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28
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Loza-Medrano SS, Baiza-Gutman LA, Manuel-Apolinar L, García-Macedo R, Damasio-Santana L, Martínez-Mar OA, Sánchez-Becerra MC, Cruz-López M, Ibáñez-Hernández MA, Díaz-Flores M. High fructose-containing drinking water-induced steatohepatitis in rats is prevented by the nicotinamide-mediated modulation of redox homeostasis and NADPH-producing enzymes. Mol Biol Rep 2019; 47:337-351. [PMID: 31650383 DOI: 10.1007/s11033-019-05136-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 10/10/2019] [Indexed: 01/15/2023]
Abstract
An imbalance in the redox state, increased levels of lipid precursors and overactivation of de novo lipogenesis determine the development of fibrosis during nonalcoholic steatohepatitis (NASH). We evaluated the modulation of NADPH-producing enzymes associated with the antifibrotic, antioxidant and antilipemic effects of nicotinamide (NAM) in a model of NASH induced by excess fructose consumption. Male rats were provided drinking water containing 40% fructose for 16 weeks. During the last 12 weeks of fructose administration, water containing NAM was provided to some of the rats for 5 h/day. The biochemical profiles and the ghrelin, leptin, lipoperoxidation and TNF-α levels in serum and the glucose-6-phosphate dehydrogenase (G6PD), malic enzyme (ME) and NADP+-dependent isocitric dehydrogenase (IDP) levels, the reduced/oxidized glutathione (GSH/GSSG) and reduced/oxidized nicotinamide adenine dinucleotide (phosphate) (NAD(P)H/NAD(P)+) ratios, and the levels of various lipogenic and fibrotic markers in the liver were evaluated. The results showed that hepatic fibrosis induced by fructose consumption was associated with weight gain, hunger-satiety system dysregulation, hyperinsulinemia, dyslipidemia, lipoperoxidation and inflammation. Moreover, increased levels of hepatic G6PD and ME activity and expression, the NAD(P)H/NAD(P)+ ratios, and GSSG concentration and increased expression of lipogenic and fibrotic markers were detected, and these alterations were attenuated by NAM administration. Specifically, NAM diminished the activity and expression of G6PD and ME, and this effect was associated with a decrease in the NADPH/NADP+ ratios, increased GSH levels and decreased lipoperoxidation and inflammation, ameliorating fibrosis and NASH development. NAM reduces liver steatosis and fibrosis by regulating redox homeostasis through a G6PD- and ME-dependent mechanism.
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Affiliation(s)
- S S Loza-Medrano
- Posgrado en Biomedicina y Biotecnología Molecular, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México City, Mexico.,Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades (1er. Piso), "Bernardo Sepúlveda" Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, C.P. 06725, México City, Mexico
| | - L A Baiza-Gutman
- Laboratorio en Biología del Desarrollo, Unidad de Morfología y Función, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Estado de México, Mexico
| | - L Manuel-Apolinar
- Unidad de Investigación Médica en Enfermedades Endocrinas, Hospital de Especialidades "Bernardo Sepúlveda" Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México City, Mexico
| | - R García-Macedo
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades (1er. Piso), "Bernardo Sepúlveda" Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, C.P. 06725, México City, Mexico
| | - L Damasio-Santana
- Unidad de Investigación Médica en Enfermedades Endocrinas, Hospital de Especialidades "Bernardo Sepúlveda" Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México City, Mexico
| | - O A Martínez-Mar
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades (1er. Piso), "Bernardo Sepúlveda" Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, C.P. 06725, México City, Mexico
| | - M C Sánchez-Becerra
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades (1er. Piso), "Bernardo Sepúlveda" Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, C.P. 06725, México City, Mexico
| | - M Cruz-López
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades (1er. Piso), "Bernardo Sepúlveda" Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, C.P. 06725, México City, Mexico
| | - M A Ibáñez-Hernández
- Laboratorio de Terapia Génica, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México City, Mexico
| | - M Díaz-Flores
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades (1er. Piso), "Bernardo Sepúlveda" Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, C.P. 06725, México City, Mexico.
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Männistö V, Kaminska D, Kärjä V, Tiainen M, de Mello VD, Hanhineva K, Soininen P, Ala-Korpela M, Pihlajamäki J. Total liver phosphatidylcholine content associates with non-alcoholic steatohepatitis and glycine N-methyltransferase expression. Liver Int 2019; 39:1895-1905. [PMID: 31199045 DOI: 10.1111/liv.14174] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 05/27/2019] [Accepted: 06/04/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Alterations in liver phosphatidylcholine (PC) metabolism have been implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Although genetic variation in the phosphatidylethanolamine N-methyltransferase (PEMT) enzyme synthesizing PC has been associated with disease, the functional mechanism linking PC metabolism to the pathogenesis of non-alcoholic steatohepatitis (NASH) remains unclear. METHODS Serum PC levels and liver PC contents were measured using proton nuclear magnetic resonance (NMR) spectroscopy in 169 obese individuals [age 46.6 ± 10 (mean ± SD) years, BMI 43.3 ± 6 kg/m2 , 53 men and 116 women] with histological assessment of NAFLD; 106 of these had a distinct liver phenotype. All subjects were genotyped for PEMT rs7946 and liver mRNA expression of PEMT and glycine N-methyltransferase (GNMT) was analysed. RESULTS Liver PC content was lower in those with NASH (P = 1.8 x 10-6 ) while serum PC levels did not differ between individuals with NASH and normal liver (P = 0.591). Interestingly, serum and liver PC did not correlate (rs = -0.047, P = 0.557). Serum PC and serum cholesterol levels correlated strongly (rs = 0.866, P = 7.1 x 10-49 ), while liver PC content did not correlate with serum cholesterol (rs = 0.065, P = 0.413). Neither PEMT V175M genotype nor PEMT expression explained the association between liver PC content and NASH. Instead, liver GNMT mRNA expression was decreased in those with NASH (P = 3.8 x 10-4 ) and correlated with liver PC content (rs = 0.265, P = 0.001). CONCLUSIONS Decreased liver PC content in individuals with the NASH is independent of PEMT V175M genotype and could be partly linked to decreased GNMT expression.
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Affiliation(s)
- Ville Männistö
- Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Dorota Kaminska
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Vesa Kärjä
- Department of Pathology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Mika Tiainen
- NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Vanessa D de Mello
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Kati Hanhineva
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.,LC-MS Metabolomics Center, Biocenter Kuopio, Kuopio, Finland
| | - Pasi Soininen
- NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Mika Ala-Korpela
- NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.,Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, Vic., Australia.,Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.,Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK.,Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.,Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, The Alfred Hospital, Monash University, Melbourne, Vic., Australia
| | - Jussi Pihlajamäki
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.,Clinical Nutrition and Obesity Center, Kuopio University Hospital, Kuopio, Finland
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30
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Pan S, Leng J, Deng X, Ruan H, Zhou L, Jamal M, Xiao R, Xiong J, Yin Q, Wu Y, Wang M, Yuan W, Shao L, Zhang Q. Nicotinamide increases the sensitivity of chronic myeloid leukemia cells to doxorubicin via the inhibition of SIRT1. J Cell Biochem 2019; 121:574-586. [PMID: 31407410 DOI: 10.1002/jcb.29303] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 06/27/2019] [Indexed: 12/13/2022]
Abstract
The NAD-dependent deacetylase Sirtuin 1 (SIRT1) plays a vital role in leukemogenesis. Nicotinamide (NAM) is the principal NAD+ precursor and a noncompetitive inhibitor of SIRT1. In our study, we showed that NAM enhanced the sensitivity of chronic myeloid leukemia (CML) to doxorubicin (DOX) via SIRT1. We found that SIRT1 high expression in CML patients was associated with disease progression and drug resistance. Exogenous NAM efficiently repressed the deacetylation activity of SIRT1 and induced the apoptosis of DOX-resistant K562 cells (K562R) in a dose-dependent manner. Notably, the combination of NAM and DOX significantly inhibited tumor cell proliferation and induced cell apoptosis. The knockdown of SIRT1 in K562R cells enhanced NAM+DOX-induced apoptosis. SIRT1 rescue in K562R reduced the NAM+DOX-induced apoptosis. Mechanistically, the combinatory treatment significantly increased the cleavage of caspase-3 and PARP in K562R in vitro and in vivo. These results suggest the potential role of NAM in increasing the sensitivity of CML to DOX via the inhibition of SIRT1.
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Affiliation(s)
- Shan Pan
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China
| | - Jun Leng
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China
| | - Xinzhou Deng
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China
| | - Honggang Ruan
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China
| | - Lu Zhou
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China
| | - Muhammad Jamal
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China
| | - Ruijing Xiao
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China
| | - Jie Xiong
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China
| | - Qian Yin
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China
| | - Yingjie Wu
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China
| | - Meng Wang
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China
| | - Wen Yuan
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China
| | - Liang Shao
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Qiuping Zhang
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China.,Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University, Wuhan, China
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31
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Zheng M, Cai J, Liu Z, Shu S, Wang Y, Tang C, Dong Z. Nicotinamide reduces renal interstitial fibrosis by suppressing tubular injury and inflammation. J Cell Mol Med 2019; 23:3995-4004. [PMID: 30993884 PMCID: PMC6533567 DOI: 10.1111/jcmm.14285] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 02/12/2019] [Accepted: 03/01/2019] [Indexed: 12/14/2022] Open
Abstract
Renal interstitial fibrosis is a common pathological feature in progressive kidney diseases currently lacking effective treatment. Nicotinamide (NAM), a member of water‐soluble vitamin B family, was recently suggested to have a therapeutic potential for acute kidney injury (AKI) in mice and humans. The effect of NAM on chronic kidney pathologies, including renal fibrosis, is unknown. Here we have tested the effects of NAM on renal interstitial fibrosis using in vivo and in vitro models. In vivo, unilateral urethral obstruction (UUO) induced renal interstitial fibrosis as indicated Masson trichrome staining and expression of pro‐fibrotic proteins, which was inhibited by NAM. In UUO, NAM suppressed tubular atrophy and apoptosis. In addition, NAM suppressed UUO‐associated T cell and macrophage infiltration and induction of pro‐inflammatory cytokines, such as TNF‐α and IL‐1β. In cultured mouse proximal tubule cells, NAM blocked TGF–β‐induced expression of fibrotic proteins, while it marginally suppressed the morphological changes induced by TGF‐β. NAM also suppressed the expression of pro‐inflammatory cytokines (eg MCP‐1 and IL‐1β) during TGF‐β treatment of these cells. Collectively, the results demonstrate an anti‐fibrotic effect of NAM in kidneys, which may involve the suppression of tubular injury and inflammation.
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Affiliation(s)
- Meiling Zheng
- Department of Nephrology, The Key Laboratory of Kidney Disease and Blood Purification of Hunan Province, Second Xiangya Hospital at Central South University, Changsha, China.,The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China
| | - Juan Cai
- Department of Nephrology, The Key Laboratory of Kidney Disease and Blood Purification of Hunan Province, Second Xiangya Hospital at Central South University, Changsha, China
| | - Zhiwen Liu
- Department of Nephrology, The Key Laboratory of Kidney Disease and Blood Purification of Hunan Province, Second Xiangya Hospital at Central South University, Changsha, China
| | - Shaoqun Shu
- Department of Nephrology, The Key Laboratory of Kidney Disease and Blood Purification of Hunan Province, Second Xiangya Hospital at Central South University, Changsha, China
| | - Ying Wang
- Department of Nephrology, The Key Laboratory of Kidney Disease and Blood Purification of Hunan Province, Second Xiangya Hospital at Central South University, Changsha, China
| | - Chengyuan Tang
- Department of Nephrology, The Key Laboratory of Kidney Disease and Blood Purification of Hunan Province, Second Xiangya Hospital at Central South University, Changsha, China
| | - Zheng Dong
- Department of Nephrology, The Key Laboratory of Kidney Disease and Blood Purification of Hunan Province, Second Xiangya Hospital at Central South University, Changsha, China
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Wang K, Fang S, Liu Q, Gao J, Wang X, Zhu H, Zhu Z, Ji F, Wu J, Ma Y, Hu L, Shen X, Gao D, Zhu J, Liu P, Zhou H. TGF-β1/p65/MAT2A pathway regulates liver fibrogenesis via intracellular SAM. EBioMedicine 2019; 42:458-469. [PMID: 30926424 PMCID: PMC6491716 DOI: 10.1016/j.ebiom.2019.03.058] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 03/13/2019] [Accepted: 03/19/2019] [Indexed: 12/15/2022] Open
Abstract
Background Hepatic stellate cell (HSC) activation induced by transforming growth factor β1 (TGF-β1) plays a pivotal role in fibrogenesis, while the complex downstream mediators of TGF-β1 in such process are largely unknown. Methods We performed pharmacoproteomic profiling of the mice liver tissues from control, carbon tetrachloride (CCl4)-induced fibrosis and NPLC0393 administrated groups. The target gene MAT2A was overexpressed or knocked down in vivo by tail vein injection of AAV vectors. We examined NF-κB transcriptional activity on MAT2A promoter via luciferase assay. Intracellular SAM contents were analyzed by LC-MS method. Findings We found that methionine adenosyltransferase 2A (MAT2A) is significantly upregulated in the CCl4-induced fibrosis mice, and application of NPLC0393, a known small molecule inhibitor of TGF-β1 signaling pathway, inhibits the upregulation of MAT2A. Mechanistically, TGF-β1 induces phosphorylation of p65, i.e., activation of NF-κB, thereby promoting mRNA transcription and protein expression of MAT2A and reduces S-adenosylmethionine (SAM) concentration in HSCs. Consistently, in vivo and in vitro knockdown of MAT2A alleviates CCl4- and TGF-β1-induced HSC activation, whereas in vivo overexpression of MAT2A facilitates hepatic fibrosis and abolishes therapeutic effect of NPLC0393. Interpretation This study identifies TGF-β1/p65/MAT2A pathway that is involved in the regulation of intracellular SAM concentration and liver fibrogenesis, suggesting that this pathway is a potential therapeutic target for hepatic fibrosis. Fund This work was supported by National Natural Science Foundation of China (No. 81500469, 81573873, 81774196 and 31800693), Zhejiang Provincial Natural Science Foundation of China (No. Y15H030004), the National Key Research and Development Program from the Ministry of Science and Technology of China (No. 2017YFC1700200) and the Key Program of National Natural Science Foundation of China (No. 8153000502).
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Affiliation(s)
- Kuifeng Wang
- Department of Infectious Diseases, Affiliated Taizhou Hospital of Wenzhou Medical University, 150 Ximen Road of Linhai City, Taizhou 317000, China; Suzhou GenHouse Pharmaceutical Co., Ltd., 388 Ruoshui Road, Suzhou, Jiangsu 215123, China
| | - Shanhua Fang
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; E-Institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China
| | - Qian Liu
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China
| | - Jing Gao
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Xiaoning Wang
- E-Institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China; Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Department of Pharmacology, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China
| | - Hongwen Zhu
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Zhenyun Zhu
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Feihong Ji
- Department of Infectious Diseases, Affiliated Taizhou Hospital of Wenzhou Medical University, 150 Ximen Road of Linhai City, Taizhou 317000, China; Suzhou GenHouse Pharmaceutical Co., Ltd., 388 Ruoshui Road, Suzhou, Jiangsu 215123, China
| | - Jiasheng Wu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Department of Pharmacology, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China
| | - Yueming Ma
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Department of Pharmacology, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China
| | - Lihong Hu
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China; State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China
| | - Xu Shen
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China; State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China
| | - Daming Gao
- CAS Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
| | - Jiansheng Zhu
- Department of Infectious Diseases, Affiliated Taizhou Hospital of Wenzhou Medical University, 150 Ximen Road of Linhai City, Taizhou 317000, China.
| | - Ping Liu
- E-Institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China; Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Department of Pharmacology, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai 201203, China.
| | - Hu Zhou
- Department of Analytical Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; E-Institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
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Hughey CC, James FD, Wang Z, Goelzer M, Wasserman DH. Dysregulated transmethylation leading to hepatocellular carcinoma compromises redox homeostasis and glucose formation. Mol Metab 2019; 23:1-13. [PMID: 30850319 PMCID: PMC6479583 DOI: 10.1016/j.molmet.2019.02.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 02/18/2019] [Accepted: 02/20/2019] [Indexed: 12/24/2022] Open
Abstract
Objective The loss of liver glycine N-methyltransferase (GNMT) promotes liver steatosis and the transition to hepatocellular carcinoma (HCC). Previous work showed endogenous glucose production is reduced in GNMT-null mice with gluconeogenic precursors being used in alternative biosynthetic pathways that utilize methyl donors and are linked to tumorigenesis. This metabolic programming occurs before the appearance of HCC in GNMT-null mice. The metabolic physiology that sustains liver tumor formation in GNMT-null mice is unknown. The studies presented here tested the hypothesis that nutrient flux pivots from glucose production to pathways that incorporate and metabolize methyl groups in GNMT-null mice with HCC. Methods 2H/13C metabolic flux analysis was performed in conscious, unrestrained mice lacking GNMT to quantify glucose formation and associated nutrient fluxes. Molecular analyses of livers from mice lacking GNMT including metabolomic, immunoblotting, and immunochemistry were completed to fully interpret the nutrient fluxes. Results GNMT knockout (KO) mice showed lower blood glucose that was accompanied by a reduction in liver glycogenolysis and gluconeogenesis. NAD+ was lower and the NAD(P)H-to-NAD(P)+ ratio was higher in livers of KO mice. Indices of NAD+ synthesis and catabolism, pentose phosphate pathway flux, and glutathione synthesis were dysregulated in KO mice. Conclusion Glucose precursor flux away from glucose formation towards pathways that regulate redox status increase in the liver. Moreover, synthesis and scavenging of NAD+ are both impaired resulting in reduced concentrations. This metabolic program blunts an increase in methyl donor availability, however, biosynthetic pathways underlying HCC are activated.
Loss of glycine N-methyltransferase results in hepatocellular carcinoma. Metabolic reprogramming ensues to attenuate the increased S-adenosylmethionine. The metabolic changes include dysregulated liver NAD+ homeostasis and redox state. Liver glucose formation is reduced and precursors directed to biosynthetic pathways.
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Affiliation(s)
- Curtis C Hughey
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA.
| | - Freyja D James
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA; Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN, USA
| | - Zhizhang Wang
- Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN, USA
| | - Mickael Goelzer
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA
| | - David H Wasserman
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA; Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN, USA
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Hepatic accumulation of S-adenosylmethionine in hamsters with non-alcoholic fatty liver disease associated with metabolic syndrome under selenium and vitamin E deficiency. Clin Sci (Lond) 2019; 133:409-423. [PMID: 29122967 DOI: 10.1042/cs20171039] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 10/27/2017] [Accepted: 11/09/2017] [Indexed: 12/13/2022]
Abstract
Progression of non-alcoholic fatty liver disease (NAFLD) in the context of metabolic syndrome (MetS) is only partially explored due to the lack of preclinical models. In order to study the alterations in hepatic metabolism that accompany this condition, we developed a model of MetS accompanied by the onset of steatohepatitis (NASH) by challenging golden hamsters with a high-fat diet low in vitamin E and selenium (HFD), since combined deficiency results in hepatic necroinflammation in rodents. Metabolomics and transcriptomics integrated analyses of livers revealed an unexpected accumulation of hepatic S-Adenosylmethionine (SAM) when compared with healthy livers likely due to diminished methylation reactions and repression of GNMT. SAM plays a key role in the maintenance of cellular homeostasis and cell cycle control. In agreement, analysis of over-represented transcription factors revealed a central role of c-myc and c-Jun pathways accompanied by negative correlations between SAM concentration, MYC expression and AMPK phosphorylation. These findings point to a drift of cell cycle control toward senescence in livers of HFD animals, which could explain the onset of NASH in this model. In contrast, hamsters with NAFLD induced by a conventional high-fat diet did not show SAM accumulation, suggesting a key role of selenium and vitamin E in SAM homeostasis. In conclusion, our results suggest that progression of NAFLD in the context of MetS can take place even in a situation of hepatic SAM excess and that selenium and vitamin E status might be considered in current therapies against NASH based on SAM supplementation.
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ZNF300 stimulates fatty acid oxidation and alleviates hepatosteatosis through regulating PPARα. Biochem J 2019; 476:385-404. [PMID: 30568000 DOI: 10.1042/bcj20180517] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Revised: 12/05/2018] [Accepted: 12/19/2018] [Indexed: 02/07/2023]
Abstract
ZNF300 plays an important role in the regulation of HBV-related hepatocellular carcinoma. However, little is known about the role of ZNF300 in lipid metabolism and NAFLD. In the present study, we observed that ZNF300 expression was markedly decreased in free fatty acid (FFA)-induced fatty liver. Overexpressed ZNF300 alleviated hepatic lipid accumulation, whereas knockdown of ZNF300 enhanced the FFA-induced lipid accumulation. Investigations of the underlying mechanisms revealed that ZNF300 directly binds to and regulates the PPARα expression, thus promoting fatty acid oxidation. Furthermore, bisulfite pyrosequencing PCR (BSP) analysis identified the hypermethylation status of ZNF300 gene in FFA-treated hepatocytes. Importantly, the suppression of ZNF300 could be blocked by DNA methyltransferase inhibitor (5-azadC) or DNMT3a-siRNA. These results suggested that ZNF300 plays an important role in hepatic lipid metabolism via PPARα promoting fatty acid oxidation and this effect might be blocked by DNMT3a-mediated methylation of ZNF300. Therefore, in addition to ZNF300 expression levels, the methylation status of this gene also has a potential as a prognostic biomarker.
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Li MH, Feng X, Deng Ba DJ, Chen C, Ruan LY, Xing YX, Chen LY, Zhong GJ, Wang JS. Hepatoprotection of Herpetospermum caudigerum Wall. against CCl 4-induced liver fibrosis on rats. JOURNAL OF ETHNOPHARMACOLOGY 2019; 229:1-14. [PMID: 30268654 DOI: 10.1016/j.jep.2018.09.033] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 09/18/2018] [Accepted: 09/26/2018] [Indexed: 06/08/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Herpetospermum caudigerum Wall. (HCW) is a traditional Tibetan medicine, which has been used to ameliorate liver injuries in the folk. AIM OF THE STUDY Liver fibrosis has been recognized as a major lesion of the liver that leads to liver cirrhosis/hepatocarcinoma and even to death in the end. This study aims to demonstrate the protective effect of HCW against CCl4-induced liver injury in rats and to explore the underlying mechanisms. MATERIALS AND METHODS Hepatic fibrosis was induced by intraperitoneal injection of CCl4. Liver function markers, fibrosis markers, serum anti-oxidation enzymes as well as elements levels were determined. Serum and liver tissues were subjected to NMR-based metabolomics and multivariate statistical analysis. RESULTS HCW could significantly reduce the elevated levels of fibrosis markers such as hyaluronidase, laminin, Type III procollagen and Type IV collagen in the serum, improve the activities of the antioxidant enzymes, and effectively reverse the abnormal levels of elements in liver fibrosis rats. Correlation network analysis revealed that HCW could treat liver fibrosis by ameliorating oxidative stress, repairing the impaired energy metabolisms and reversing the disturbed amino acids and nucleic acids metabolisms. CONCLUSION This integrated metabolomics approach confirmed the validity of the traditional use of HCW in the treatment of liber fibrosis, providing new insights into the underlying mechanisms.
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Affiliation(s)
- Ming-Hui Li
- Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing 210094, People's Republic of China; School of Life Sciences, Anhui Normal University, No. 1 Beijing East Road, Wuhu 241000, People's Republic of China.
| | - Xin Feng
- Tibetan Medicine Institute, China Tibetology Research Center, Beijing 100101, People's Republic of China.
| | - Da Ji Deng Ba
- Tibetan Medicine Institute, China Tibetology Research Center, Beijing 100101, People's Republic of China.
| | - Cheng Chen
- Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing 210094, People's Republic of China.
| | - Ling-Yu Ruan
- Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing 210094, People's Republic of China.
| | - Yue-Xiao Xing
- Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing 210094, People's Republic of China.
| | - Lv-Yi Chen
- School of Pharmacy, South-Central University for Nationalities, 182 National Road, Wuhan 430074, People's Republic of China.
| | - Ge-Jia Zhong
- Tibetan Medicine Institute, China Tibetology Research Center, Beijing 100101, People's Republic of China.
| | - Jun-Song Wang
- Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing 210094, People's Republic of China.
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Ostrakhovitch EA, Tabibzadeh S. Homocysteine and age-associated disorders. Ageing Res Rev 2019; 49:144-164. [PMID: 30391754 DOI: 10.1016/j.arr.2018.10.010] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 09/30/2018] [Accepted: 10/25/2018] [Indexed: 12/26/2022]
Abstract
There are numerous theories of aging, a process which still seems inevitable. Aging leads to cancer and multi-systemic disorders as well as chronic diseases. Decline in age- associated cellular functions leads to neurodegeneration and cognitive decline that affect the quality of life. Accumulation of damage, mutations, metabolic changes, failure in cellular energy production and clearance of altered proteins over the lifetime, and hyperhomocysteinemia, ultimately result in tissue degeneration. The decline in renal functions, nutritional deficiencies, deregulation of methionine cycle and deficiencies of homocysteine remethylation and transsulfuration cofactors cause elevation of homocysteine with advancing age. Abnormal accumulation of homocysteine is a risk factor of cardiovascular, neurodegenerative and chronic kidney disease. Moreover, approximately 50% of people, aged 65 years and older develop hypertension and are at a high risk of developing cardiovascular insufficiency and incurable neurodegenerative disorders. Increasing evidence suggests inverse relation between cognitive impairment, cerebrovascular and cardiovascular events and renal function. Oxidative stress, inactivation of nitric oxide synthase pathway and mitochondria dysfunction associated with impaired homocysteine metabolism lead to aging tissue degeneration. In this review, we examine impact of high homocysteine levels on changes observed with aging that contribute to development and progression of age associated diseases.
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Affiliation(s)
- E A Ostrakhovitch
- Frontiers in Bioscience Research Institute in Aging and Cancer, Irvine, CA, USA.
| | - S Tabibzadeh
- Frontiers in Bioscience Research Institute in Aging and Cancer, Irvine, CA, USA.
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38
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Ferrari A, Longo R, Silva R, Mitro N, Caruso D, De Fabiani E, Crestani M. Epigenome modifiers and metabolic rewiring: New frontiers in therapeutics. Pharmacol Ther 2019; 193:178-193. [DOI: 10.1016/j.pharmthera.2018.08.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Hong S, Zhai B, Pissios P. Nicotinamide N-Methyltransferase Interacts with Enzymes of the Methionine Cycle and Regulates Methyl Donor Metabolism. Biochemistry 2018; 57:5775-5779. [PMID: 30226369 DOI: 10.1021/acs.biochem.8b00561] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Methyl donor balance is critical for epigenetic regulation in cells and is maintained by the so-called methionine cycle proteins that regenerate S-adenosylmethionine (SAM), the universal methyl donor, from homocysteine formed by the activity of methyltransferases. Nnmt is a liver enzyme that methylates nicotinamide, but its role in regulating methyl donor balance in the liver is unclear. In this study, we assessed the effect of altered Nnmt expression on various aspects of methyl donor metabolism in the liver. We found that Nnmt overexpression decreased SAM levels and the SAM/ S-adenosylhomocysteine (SAH) ratio both in vivo and in vitro. Nnmt knockdown did not change methyl donor balance in mouse primary hepatocytes but increased SAM levels and the SAM/SAH ratio when Gnmt, the dominantly expressed methyltransferase in liver, was simultaneously knocked down. Paradoxically, expression of enzymatically deficient Nnmt increased the SAM/SAH ratio, suggesting that Nnmt can regulate methyl donor balance independent of its methyltransferase activity. Proteomics analysis of Nnmt-interacting proteins in the liver identified Bhmt, Mat1a, and Ahcy, all components of the methionine cycle, and functional experiments showed that mutant Nnmt increased the level of remethylation of homocysteine to SAM. In summary, we show that the function of Nnmt in hepatic methyl donor balance is multifactorial. On one hand, Nnmt decreases methyl donor balance, consistent with its activity as a methyltransferase consuming methyl donors. On the other hand, by co-opting the enzymes of the methionine cycle, Nnmt aids the recycling of homocysteine to SAM for another round of methylation.
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Affiliation(s)
- Shangyu Hong
- State Key Laboratory of Genetic Engineering and School of Life Sciences, Collaborative Innovation Center for Genetics and Development , Fudan University , Shanghai 200438 , China.,Division of Endocrinology, Diabetes and Metabolism , Beth Israel Deaconess Medical Center , Boston , Massachusetts 02215 , United States
| | - Bo Zhai
- Department of Cell Biology , Harvard Medical School , Boston , Massachusetts 02215 , United States
| | - Pavlos Pissios
- Division of Endocrinology, Diabetes and Metabolism , Beth Israel Deaconess Medical Center , Boston , Massachusetts 02215 , United States
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40
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Jin C, Zhuo Y, Wang J, Zhao Y, Xuan Y, Mou D, Liu H, Zhou P, Fang Z, Che L, Xu S, Feng B, Li J, Jiang X, Lin Y, Wu D. Methyl donors dietary supplementation to gestating sows diet improves the growth rate of offspring and is associating with changes in expression and DNA methylation of insulin-like growth factor-1 gene. J Anim Physiol Anim Nutr (Berl) 2018; 102:1340-1350. [PMID: 29959805 DOI: 10.1111/jpn.12933] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 04/27/2018] [Accepted: 05/06/2018] [Indexed: 01/08/2023]
Abstract
The study aimed to investigate the effects of maternal dietary methyl donors on the performance of sows and their offspring, and the associated hepatic insulin-like growth factor-1 (IGF-1) expression of the offspring. A total of 24 multiparous sows were randomly fed the control (CON) or the CON diet supplemented with methyl donors (MD) at 3 g/kg betaine, 15 mg/kg folic acid, 400 mg/kg choline and 150 μg/kg VB12 , from mating until delivery. After farrowing, sows were fed a common lactation diet through a 28-days lactation period and six litters per treatment were selected to be fed until at approximately 110 kg BW. Maternal MD supplementation resulted in greater birthweight (p < 0.05) and increased the piglet weights (p < 0.01) and litter weights (p < 0.05) at the age of day 28, compared with that in CON group. The offspring pigs in the MD group had greater ADG (p < 0.05) and tended to lower F:G ratio (p = 0.07) compared with that of CON group from day 28 to 180 of age. The offspring pigs from MD group had greater serum IGF-1 concentrations and expressions of hepatic IGF-1 gene and muscular IGF-1 receptor (IGF-1r) protein at birth (p < 0.05), and greater hepatic IGF-1 protein (p = 0.03) and muscular IGF-1r gene expressions (p < 0.05) at slaughter, than that from the CON group. Moreover, the methylation at the promoter of IGF-1 gene in the liver of newborn piglets and finishing pigs was greater in the MD group than that of the CON group (p < 0.05). In conclusion, maternal MD supplementation throughout gestation could enhance the birthweight and postnatal growth rate of offspring, associated with an increased expression of the IGF-1 gene and IGF-1r, as well as the altered DNA methylation of IGF-1 gene promotor.
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Affiliation(s)
- Chao Jin
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Yong Zhuo
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Jun Wang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Yang Zhao
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Yuedong Xuan
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Daolin Mou
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Hong Liu
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Pan Zhou
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Zhengfeng Fang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Lianqiang Che
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Shengyu Xu
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Bin Feng
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Jian Li
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Xuemei Jiang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Yan Lin
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - De Wu
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education of China, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
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41
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Hughey CC, Trefts E, Bracy DP, James FD, Donahue EP, Wasserman DH. Glycine N-methyltransferase deletion in mice diverts carbon flux from gluconeogenesis to pathways that utilize excess methionine cycle intermediates. J Biol Chem 2018; 293:11944-11954. [PMID: 29891549 DOI: 10.1074/jbc.ra118.002568] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 05/17/2018] [Indexed: 12/19/2022] Open
Abstract
Glycine N-methyltransferase (GNMT) is the most abundant liver methyltransferase regulating the availability of the biological methyl donor, S-adenosylmethionine (SAM). Moreover, GNMT has been identified to be down-regulated in hepatocellular carcinoma (HCC). Despite its role in regulating SAM levels and association of its down-regulation with liver tumorigenesis, the impact of reduced GNMT on metabolic reprogramming before the manifestation of HCC has not been investigated in detail. Herein, we used 2H/13C metabolic flux analysis in conscious, unrestrained mice to test the hypothesis that the absence of GNMT causes metabolic reprogramming. GNMT-null (KO) mice displayed a reduction in blood glucose that was associated with a decline in both hepatic glycogenolysis and gluconeogenesis. The reduced gluconeogenesis was due to a decrease in liver gluconeogenic precursors, citric acid cycle fluxes, and anaplerosis and cataplerosis. A concurrent elevation in both hepatic SAM and metabolites of SAM utilization pathways was observed in the KO mice. Specifically, the increase in metabolites of SAM utilization pathways indicated that hepatic polyamine synthesis and catabolism, transsulfuration, and de novo lipogenesis pathways were increased in the KO mice. Of note, these pathways utilize substrates that could otherwise be used for gluconeogenesis. Also, this metabolic reprogramming occurs before the well-documented appearance of HCC in GNMT-null mice. Together, these results indicate that GNMT deletion promotes a metabolic shift whereby nutrients are channeled away from glucose formation toward pathways that utilize the elevated SAM.
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Affiliation(s)
- Curtis C Hughey
- From the Department of Molecular Physiology and Biophysics and
| | - Elijah Trefts
- From the Department of Molecular Physiology and Biophysics and
| | - Deanna P Bracy
- From the Department of Molecular Physiology and Biophysics and.,the Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, Tennessee 37232
| | - Freyja D James
- From the Department of Molecular Physiology and Biophysics and.,the Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, Tennessee 37232
| | | | - David H Wasserman
- From the Department of Molecular Physiology and Biophysics and.,the Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, Tennessee 37232
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42
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Komatsu M, Kanda T, Urai H, Kurokochi A, Kitahama R, Shigaki S, Ono T, Yukioka H, Hasegawa K, Tokuyama H, Kawabe H, Wakino S, Itoh H. NNMT activation can contribute to the development of fatty liver disease by modulating the NAD + metabolism. Sci Rep 2018; 8:8637. [PMID: 29872122 PMCID: PMC5988709 DOI: 10.1038/s41598-018-26882-8] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Accepted: 05/22/2018] [Indexed: 12/15/2022] Open
Abstract
Nicotinamide N-methyltransferase (NNMT) catalyses the reaction between nicotinamide (NAM) and S-adenosylmethionine to produce 1-methylnicotinamide and S-adenosylhomocysteine. Recently, this enzyme has also been reported to modulate hepatic nutrient metabolism, but its role in the liver has not been fully elucidated. We developed transgenic mice overexpressing NNMT to elucidate its role in hepatic nutrient metabolism. When fed a high fat diet containing NAM, a precursor for nicotinamide adenine dinucleotide (NAD)+, these NNMT-overexpressing mice exhibit fatty liver deterioration following increased expression of the genes mediating fatty acid uptake and decreased very low-density lipoprotein secretion. NNMT overactivation decreased the NAD+ content in the liver and also decreased gene activity related to fatty acid oxidation by inhibiting NAD+-dependent deacetylase Sirt3 function. Moreover, the transgenic mice showed liver fibrosis, with the induction of inflammatory and fibrosis genes. Induced NNMT expression decreased the tissue methylation capacity, thereby reducing methylation of the connective tissue growth factor (CTGF) gene promoter, resulting in increased CTGF expression. These data indicate that NNMT links the NAD+ and methionine metabolic pathways and promotes liver steatosis and fibrosis. Therefore, targeting NNMT may serve as a therapeutic strategy for treating fatty liver and fibrosis.
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Affiliation(s)
- Motoaki Komatsu
- Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan
| | - Takeshi Kanda
- Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan
| | - Hidenori Urai
- Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan
| | - Arata Kurokochi
- Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan
| | - Rina Kitahama
- Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan
| | | | | | | | - Kazuhiro Hasegawa
- Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan
| | - Hirobumi Tokuyama
- Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan
| | | | - Shu Wakino
- Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
| | - Hiroshi Itoh
- Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan
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43
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Chang MM, Lin CN, Fang CC, Chen M, Liang PI, Li WM, Yeh BW, Cheng HC, Huang BM, Wu WJ, Chen YMA. Glycine N-methyltransferase inhibits aristolochic acid nephropathy by increasing CYP3A44 and decreasing NQO1 expression in female mouse hepatocytes. Sci Rep 2018; 8:6960. [PMID: 29725048 PMCID: PMC5934382 DOI: 10.1038/s41598-018-22298-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 02/19/2018] [Indexed: 12/12/2022] Open
Abstract
Plants containing aristolochic acids (AA) are nephrotoxins. Glycine N-methyltransferase (GNMT) acts to bind environmental toxins such as benzo(a)pyrene and aflatoxin B1, translocate into nucleus, and alter hepatic metabolism. This study aims to determine the role of GNMT in AA-induced nephropathy. We established an AA nephropathy mouse model and found that AA type I (AAI)-induced nephropathy at a lower concentration in male than in female mice, implying sex differences in AAI resistance. Microarray analysis and AAI-treated mouse models showed that GNMT moderately reduced AAI-induced nephropathy by lowering the upregulated level of NQO1 in male, but significantly improved the nephropathy additionally by increasing Cyp3A44/3A41 in female. The protective effects of GNMT were absent in female GNMT knockout mice, in which re-expression of hepatic GNMT significantly decreased AAI-induced nephropathy. Mechanism-wise, AAI enhanced GNMT nuclear translocation, resulting in GNMT interaction with the promoter region of the genes encoding Nrf2 and CAR/PXR, the transcription factors for NQO1 and CYP3A44/3A41, respectively. Unlike the preference for Nrf2/NQO1 transcriptions at lower levels of GNMT, overexpression of GNMT preferred CAR/PXR/CYP3A44/3A41 transcriptions and alleviated kidney injury upon AAI treatment. In summary, hepatic GNMT protected mice from AAI nephropathy by enhancing CAR/PXR/CYP3A44/3A41 transcriptions and reducing Nrf2/NQO1 transcriptions.
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Affiliation(s)
- Ming-Min Chang
- Center for Infectious Disease and Cancer Research (CICAR), Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chang-Ni Lin
- Center for Infectious Disease and Cancer Research (CICAR), Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Cheng-Chieh Fang
- Center for Infectious Disease and Cancer Research (CICAR), Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Marcelo Chen
- Center for Infectious Disease and Cancer Research (CICAR), Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Urology, Mackay Memorial Hospital, Taipei, Taiwan.,Department of Cosmetic Applications and Management, Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan
| | - Peir-In Liang
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wei-Ming Li
- Pingtung Hospital, Ministry of Health and Welfare, Executive Yuan, Pingtung, Taiwan.,Department of Urology, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Bi-Wen Yeh
- Department of Urology, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Hung-Chi Cheng
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Bu-Miin Huang
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wen-Jeng Wu
- Center for Infectious Disease and Cancer Research (CICAR), Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Urology, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.,Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Ming Arthur Chen
- Center for Infectious Disease and Cancer Research (CICAR), Kaohsiung Medical University, Kaohsiung, Taiwan. .,Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
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Mejía SÁ, Gutman LAB, Camarillo CO, Navarro RM, Becerra MCS, Santana LD, Cruz M, Pérez EH, Flores MD. Nicotinamide prevents sweet beverage-induced hepatic steatosis in rats by regulating the G6PD, NADPH/NADP + and GSH/GSSG ratios and reducing oxidative and inflammatory stress. Eur J Pharmacol 2017; 818:499-507. [PMID: 29069580 DOI: 10.1016/j.ejphar.2017.10.048] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 10/19/2017] [Accepted: 10/20/2017] [Indexed: 12/28/2022]
Abstract
The disruption of redox state homeostasis, the overexpression of lipogenic transcription factors and enzymes, and the increase in lipogenic precursors induced by sweetened beverages are determinants of the development of nonalcoholic fatty liver disease. This study evaluated the action of nicotinamide (NAM) on the expression of glucose-6-phosphate dehydrogenase (G6PD) and redox, oxidative, and inflammatory states in a model of nonalcoholic hepatic steatosis induced by high and chronic consumption of carbohydrates. Male rats were provided drinking water with 30% glucose or fructose ad libitum for 12 weeks. Additionally, 30 days after the beginning of carbohydrate administration, some rats were simultaneously provided water with 0.06% or 0.12% NAM for 5h daily over the next 8 weeks. Biochemical profiles and expression levels of G6PD, tumor necrosis factor α (TNFα), and NADPH oxidase 4 (NOX4) were evaluated together with glutathione/glutathione disulfide (GSH/GSSG) and reduced nicotinamide adenine dinucleotide (phosphate)/nicotinamide adenine dinucleotide (phosphate) [NAD(P)H/NAD(P)] ratios and thiobarbituric acid reactive substances (TBARS). The results showed that hepatic steatosis induced by the chronic consumption of glucose or fructose was associated with body weight gain and increased levels of serum glucose, insulin, triacylglycerols, free fatty acids, transaminases, and TBARS. In the liver, the expression and activity of G6PD increased along with the GSSG, TBARS, and TG concentrations. These alterations were reduced by NAM treatment through the attenuation of increases in G6PD expression and activity and in the NADPH/NADP+ ratio, thereby slowing liver steatosis. NAM prevents redox, oxidative, and inflammatory alterations induced by high carbohydrate consumption.
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Affiliation(s)
- Selene Ángeles Mejía
- División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana Unidad Iztapalapa, Ciudad de México, México; Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades "Bernardo Sepúlveda" Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México; Universidad Autónoma Metropolitana Unidad Iztapalapa, Departamento de Ciencias de la Salud, Ciudad de México, México
| | - Luis Arturo Baiza Gutman
- Laboratorio en Biología del Desarrollo, Unidad de Morfología y Función, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Estado de México, México
| | - Clara Ortega Camarillo
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades "Bernardo Sepúlveda" Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Rafael Medina Navarro
- Departamento de Metabolismo Experimental, Centro para la Investigación Biomédica de Michoacán (CIBIMI-IMSS), Michoacán, México
| | - Martha Catalina Sánchez Becerra
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades "Bernardo Sepúlveda" Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Leticia Damasio Santana
- Unidad de Investigación Médica en Enfermedades Endocrinas, Hospital de Especialidades "Bernardo Sepúlveda" Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Miguel Cruz
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades "Bernardo Sepúlveda" Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Elizabeth Hernández Pérez
- Universidad Autónoma Metropolitana Unidad Iztapalapa, Departamento de Ciencias de la Salud, Ciudad de México, México
| | - Margarita Díaz Flores
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades "Bernardo Sepúlveda" Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México.
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Abstract
A growing epidemic of nonalcoholic fatty liver disease (NAFLD) is paralleling the increase in the incidence of obesity and diabetes mellitus in countries that consume a Western diet. As NAFLD can lead to life-threatening conditions such as cirrhosis and hepatocellular carcinoma, an understanding of the factors that trigger its development and pathological progression is needed. Although by definition this disease is not associated with alcohol consumption, exposure to environmental agents that have been linked to other diseases might have a role in the development of NAFLD. Here, we focus on one class of these agents, endocrine-disrupting chemicals (EDCs), and their potential to influence the initiation and progression of a cascade of pathological conditions associated with hepatic steatosis (fatty liver). Experimental studies have revealed several potential mechanisms by which EDC exposure might contribute to disease pathogenesis, including the modulation of nuclear hormone receptor function and the alteration of the epigenome. However, many questions remain to be addressed about the causal link between acute and chronic EDC exposure and the development of NAFLD in humans. Future studies that address these questions hold promise not only for understanding the linkage between EDC exposure and liver disease but also for elucidating the molecular mechanisms that underpin NAFLD, which in turn could facilitate the development of new prevention and treatment opportunities.
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Affiliation(s)
- Charles E Foulds
- Department of Molecular and Cellular Biology, Baylor College of Medicine
- Center for Precision Environmental Health, Baylor College of Medicine
| | - Lindsey S Treviño
- Department of Molecular and Cellular Biology, Baylor College of Medicine
- Center for Precision Environmental Health, Baylor College of Medicine
| | - Brian York
- Department of Molecular and Cellular Biology, Baylor College of Medicine
- Dan L. Duncan Cancer Center, Baylor College of Medicine
| | - Cheryl L Walker
- Department of Molecular and Cellular Biology, Baylor College of Medicine
- Center for Precision Environmental Health, Baylor College of Medicine
- Dan L. Duncan Cancer Center, Baylor College of Medicine
- Department of Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, USA
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Pissios P. Nicotinamide N-Methyltransferase: More Than a Vitamin B3 Clearance Enzyme. Trends Endocrinol Metab 2017; 28:340-353. [PMID: 28291578 PMCID: PMC5446048 DOI: 10.1016/j.tem.2017.02.004] [Citation(s) in RCA: 169] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 02/01/2017] [Accepted: 02/02/2017] [Indexed: 12/18/2022]
Abstract
Nicotinamide (NAM) N-methyltransferase (NNMT) was originally identified as the enzyme responsible for the methylation of NAM, one of the forms of vitamin B3. Methylated NAM is eventually excreted from the body. Recent evidence has expanded the role of NNMT beyond clearance of excess vitamin B3. NNMT has been implicated in the regulation of multiple metabolic pathways in tissues such as adipose and liver as well as cancer cells through the consumption of methyl donors and generation of active metabolites. This review examines recent findings regarding the function of NNMT in physiology and disease and highlights potential new avenues for therapeutic intervention. Finally, key gaps in our knowledge about this enzymatic system and future areas of investigation are discussed.
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Affiliation(s)
- Pavlos Pissios
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
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47
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van der Veen JN, Kennelly JP, Wan S, Vance JE, Vance DE, Jacobs RL. The critical role of phosphatidylcholine and phosphatidylethanolamine metabolism in health and disease. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2017; 1859:1558-1572. [PMID: 28411170 DOI: 10.1016/j.bbamem.2017.04.006] [Citation(s) in RCA: 878] [Impact Index Per Article: 109.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 03/27/2017] [Accepted: 04/09/2017] [Indexed: 12/11/2022]
Abstract
Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are the most abundant phospholipids in all mammalian cell membranes. In the 1950s, Eugene Kennedy and co-workers performed groundbreaking research that established the general outline of many of the pathways of phospholipid biosynthesis. In recent years, the importance of phospholipid metabolism in regulating lipid, lipoprotein and whole-body energy metabolism has been demonstrated in numerous dietary studies and knockout animal models. The purpose of this review is to highlight the unappreciated impact of phospholipid metabolism on health and disease. Abnormally high, and abnormally low, cellular PC/PE molar ratios in various tissues can influence energy metabolism and have been linked to disease progression. For example, inhibition of hepatic PC synthesis impairs very low density lipoprotein secretion and changes in hepatic phospholipid composition have been linked to fatty liver disease and impaired liver regeneration after surgery. The relative abundance of PC and PE regulates the size and dynamics of lipid droplets. In mitochondria, changes in the PC/PE molar ratio affect energy production. We highlight data showing that changes in the PC and/or PE content of various tissues are implicated in metabolic disorders such as atherosclerosis, insulin resistance and obesity. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá.
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Affiliation(s)
- Jelske N van der Veen
- Group on the Molecular and Cell Biology of Lipids, Canada; Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, Canada
| | - John P Kennelly
- Group on the Molecular and Cell Biology of Lipids, Canada; Department of Agricultural, Food and Nutritional Science, 4-002 Li Ka Shing Centre for Heath Research Innovations, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Sereana Wan
- Group on the Molecular and Cell Biology of Lipids, Canada; Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, Canada
| | - Jean E Vance
- Group on the Molecular and Cell Biology of Lipids, Canada; Department of Medicine, University of Alberta, Edmonton, AB T6G 2S2, Canada
| | - Dennis E Vance
- Group on the Molecular and Cell Biology of Lipids, Canada; Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, Canada
| | - René L Jacobs
- Group on the Molecular and Cell Biology of Lipids, Canada; Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, Canada; Department of Agricultural, Food and Nutritional Science, 4-002 Li Ka Shing Centre for Heath Research Innovations, University of Alberta, Edmonton, AB T6G 2E1, Canada.
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48
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Characterization of gene expression profiles in HBV-related liver fibrosis patients and identification of ITGBL1 as a key regulator of fibrogenesis. Sci Rep 2017; 7:43446. [PMID: 28262670 PMCID: PMC5337978 DOI: 10.1038/srep43446] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 01/23/2017] [Indexed: 12/19/2022] Open
Abstract
Although hepatitis B virus (HBV) infection is the leading cause of liver fibrosis (LF), the mechanisms underlying liver fibrotic progression remain unclear. Here, we investigated the gene expression profiles of HBV-related LF patients. Whole genome expression arrays were used to detect gene expression in liver biopsy samples from chronically HBV infected patients. Through integrative data analysis, we identified several pathways and key genes involved in the initiation and exacerbation of liver fibrosis. Weight gene co-expression analysis revealed that integrin subunit β-like 1 (ITGBL1) was a key regulator of fibrogenesis. Functional experiments demonstrated that ITGBL1 was an upstream regulator of LF via interactions with transforming growth factor β1. In summary, we investigated the gene expression profiles of HBV-related LF patients and identified a key regulator ITGBL1. Our findings provide a foundation for future studies of gene functions and promote the development of novel antifibrotic therapies.
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49
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Barić I, Staufner C, Augoustides-Savvopoulou P, Chien YH, Dobbelaere D, Grünert SC, Opladen T, Petković Ramadža D, Rakić B, Wedell A, Blom HJ. Consensus recommendations for the diagnosis, treatment and follow-up of inherited methylation disorders. J Inherit Metab Dis 2017; 40:5-20. [PMID: 27671891 PMCID: PMC5203850 DOI: 10.1007/s10545-016-9972-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Revised: 07/25/2016] [Accepted: 07/27/2016] [Indexed: 12/24/2022]
Abstract
Inherited methylation disorders are a group of rarely reported, probably largely underdiagnosed disorders affecting transmethylation processes in the metabolic pathway between methionine and homocysteine. These are methionine adenosyltransferase I/III, glycine N-methyltransferase, S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. This paper provides the first consensus recommendations for the diagnosis and management of methylation disorders. Following search of the literature and evaluation according to the SIGN-methodology of all reported patients with methylation defects, graded recommendations are provided in a structured way comprising diagnosis (clinical presentation, biochemical abnormalities, differential diagnosis, newborn screening, prenatal diagnosis), therapy and follow-up. Methylation disorders predominantly affect the liver, central nervous system and muscles, but clinical presentation can vary considerably between and within disorders. Although isolated hypermethioninemia is the biochemical hallmark of this group of disorders, it is not always present, especially in early infancy. Plasma S-adenosylmethionine and S-adenosylhomocysteine are key metabolites for the biochemical clarification of isolated hypermethioninemia. Mild hyperhomocysteinemia can be present in all methylation disorders. Methylation disorders do not qualify as primary targets of newborn screening. A low-methionine diet can be beneficial in patients with methionine adenosyltransferase I/III deficiency if plasma methionine concentrations exceed 800 μmol/L. There is some evidence that this diet may also be beneficial in patients with S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. S-adenosylmethionine supplementation may be useful in patients with methionine adenosyltransferase I/III deficiency. Recommendations given in this article are based on general principles and in practice should be adjusted individually according to patient's age, severity of the disease, clinical and laboratory findings.
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Affiliation(s)
- Ivo Barić
- Department of Pediatrics, University Hospital Center Zagreb, Kišpatićeva 12, Rebro, 10000, Zagreb, Croatia.
- University of Zagreb, School of Medicine, Zagreb, Croatia.
| | - Christian Staufner
- Department of General Pediatrics, Division of Metabolic Medicine and Neuropediatrics, University Hospital Heidelberg, 69120, Heidelberg, Germany
| | | | - Yin-Hsiu Chien
- Department of Medical Genetics and Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Dries Dobbelaere
- Medical Reference Center for Inherited Metabolic Diseases, Jeanne de Flandre University Hospital and RADEME Research Team for Rare Metabolic and Developmental Diseases, EA 7364 CHRU Lille, 59037, Lille, France
| | | | - Thomas Opladen
- Department of General Pediatrics, Division of Metabolic Medicine and Neuropediatrics, University Hospital Heidelberg, 69120, Heidelberg, Germany
| | - Danijela Petković Ramadža
- Department of Pediatrics, University Hospital Center Zagreb, Kišpatićeva 12, Rebro, 10000, Zagreb, Croatia
| | - Bojana Rakić
- Biochemical Genetics Laboratory, BC Children's Hospital, 4500 Oak Street, Vancouver, BC, V6H 3N1, Canada
| | - Anna Wedell
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Henk J Blom
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics Adolescent Medicine and Neonatology, University Medical Centre Freiburg, Freiburg, Germany
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50
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Ruiz-Rodado V, Nicoli ER, Probert F, Smith DA, Morris L, Wassif CA, Platt FM, Grootveld M. 1H NMR-Linked Metabolomics Analysis of Liver from a Mouse Model of NP-C1 Disease. J Proteome Res 2016; 15:3511-3527. [PMID: 27503774 DOI: 10.1021/acs.jproteome.6b00238] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Clinical manifestations of Niemann-Pick type C1 (NP-C1) disease include neonatal hepatosplenomegaly and in some patients progressive liver dysfunction and failure. This study involved a 1H NMR-linked metabolomics analysis of liver samples collected from a NP-C1 disease mutant mouse model in order to explore time-dependent imbalances in metabolic pathways associated with NP-C1 liver dysfunction, including fibrosis. NP-C1 mutant (Npc1-/-; NP-C1), control (Npc1+/+; WT), and NP-C1 heterozygous mice (Npc1+/-; HET) were generated from heterozygote matings. Aqueous extracts of these liver samples collected at time points of 3, 6, 9, and 11 weeks were subjected to high-resolution NMR analysis, and multivariate (MV) metabolomics analyses of data sets acquired were performed. A MV random forests (RFs) model effectively discriminated between NP-C1 and a combined WT/HET hepatic NMR profiles with very high predictive accuracy and reliability. Key distinguishing features included significant upregulations in the hepatic concentrations of phenylalanine, tyrosine, glutamate, lysine/ornithine, valine, threonine, and hypotaurine/methionine, and diminished levels of nicotinate/niacinamide, inosine, phosphoenolpyruvate, and 3-hydroxyphenylacetate. Quantitative pathway topological analysis confirmed that imbalances in tyrosine biosynthesis, and hepatic phenylalanine, tyrosine, glutamate/glutamine, and nicotinate/niacinamide metabolism were involved in the pathogenesis of NP-C1 disease-associated liver dysfunction/damage. 1H NMR-linked metabolomics analysis provides valuable biomarker information regarding hepatic dysfunction or damage in NP-C1 disease.
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Affiliation(s)
- Victor Ruiz-Rodado
- Leicester School of Pharmacy, De Montfort University , The Gateway, Leicester LE1 9BH, United Kingdom
| | - Elena-Raluca Nicoli
- Department of Pharmacology, University of Oxford , Mansfield Road, Oxford OX1 3QT, United Kingdom
| | - Fay Probert
- Leicester School of Pharmacy, De Montfort University , The Gateway, Leicester LE1 9BH, United Kingdom
| | - David A Smith
- Department of Pharmacology, University of Oxford , Mansfield Road, Oxford OX1 3QT, United Kingdom
| | - Lauren Morris
- Department of Pharmacology, University of Oxford , Mansfield Road, Oxford OX1 3QT, United Kingdom
| | - Christopher A Wassif
- Department of Pharmacology, University of Oxford , Mansfield Road, Oxford OX1 3QT, United Kingdom.,Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH , Bethesda, Maryland 20892, United States
| | - Frances M Platt
- Department of Pharmacology, University of Oxford , Mansfield Road, Oxford OX1 3QT, United Kingdom
| | - Martin Grootveld
- Leicester School of Pharmacy, De Montfort University , The Gateway, Leicester LE1 9BH, United Kingdom
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