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      Branched chain amino acid transaminase 1 ( BCAT1) is overexpressed and hypomethylated in patients with non-alcoholic fatty liver disease who experience adverse clinical events: A pilot study

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          Abstract

          Background and objectives

          Although the burden of non-alcoholic fatty liver disease (NAFLD) continues to increase worldwide, genetic factors predicting progression to cirrhosis and decompensation in NAFLD remain poorly understood. We sought to determine whether gene expression profiling was associated with clinical decompensation and death in patients with NAFLD, and to assess whether altered DNA methylation contributes to these changes in gene expression.

          Methods

          We performed a retrospective analysis of 86 patients in the Duke NAFLD Clinical Database and Biorepository with biopsy-proven NAFLD whose liver tissue was previously evaluated for gene expression and DNA methylation using array based technologies. We assessed the prospective development of liver and cardiovascular disease related outcomes, including hepatic decompensation as identified by the development of ascites, hepatic encephalopathy, hepatocellular carcinoma, or variceal bleeding as well as stroke and myocardial infarction via medical chart review.

          Results

          Of the 86 patients, 47 had F0-F1 fibrosis and 39 had F3-F4 fibrosis at index liver biopsy. Gene expression probe sets (n = 54,675) were analyzed; 42 genes showed significant differential expression (p<0.05) and a two-fold change in expression between patients with and without any outcome. Two expression probes of the branched chain amino-acid transaminase 1 ( BCAT1) gene were upregulated (p = 0.02; fold change 2.1 and 2.2 respectively) in patients with a clinical outcome. Methylation of three of the 34 BCAT1 CpG methylation probes were significantly inversely correlated with BCAT1 expression specific to the probes predictive of clinical deterioration.

          Conclusion

          We found differential gene expression, correlated to changes in DNA methylation, at multiple BCAT1 loci in patients with cardiovascular outcomes and/or hepatic decompensation. BCAT1 catalyzes the transformation of alpha-ketoglutarate to glutamate and has been linked to the presence and severity of NAFLD, possibly through derangements in the balance between glutamate and alpha-ketoglutarate. Given the potential for BCAT1 to identify patients at risk for poor outcomes, and the potential therapeutic implications, these results should be validated in larger prospective studies.

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          Most cited references 22

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          The epidemiology of non-alcoholic fatty liver disease.

          The increase in Non-alcoholic Fatty Liver Disease (NAFLD) and the imminent disappearance of chronic viral hepatitis thanks to new and effective therapies is motivating hepatologists to change their clinical approach to chronic liver disease. NAFLD-cirrhosis or NAFLD-Hepatocellular Carcinoma (HCC) are now the second cause of liver transplantation in the USA. This short-review is focused to the epidemiology of NAFLD/Non-alchoholic Steatohepatitis (NASH), including the definition of this disease which should be revised as well discussing the prevalence, risk factors for progression, natural history and mortality. NAFLD is considered to be the hepatic manifestation of the metabolic syndrome (MS). It affects 25-30% of the general population and the risk factors are almost identical to those of MS. The natural history involves either the development of cardiovascular diseases or cirrhosis and HCC. HCC can also develop in NASH in the absence of cirrhosis (45% of cases). We conclude that an international consensus conference on the definition, natural history, policies of surveillance and new pharmacological treatments of NAFLD and NASH is urgently needed.
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            Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease.

            Several liver disorders result from perturbations in the metabolism of hepatocytes, and their underlying mechanisms can be outlined through the use of genome-scale metabolic models (GEMs). Here we reconstruct a consensus GEM for hepatocytes, which we call iHepatocytes2322, that extends previous models by including an extensive description of lipid metabolism. We build iHepatocytes2322 using Human Metabolic Reaction 2.0 database and proteomics data in Human Protein Atlas, which experimentally validates the incorporated reactions. The reconstruction process enables improved annotation of the proteomics data using the network centric view of iHepatocytes2322. We then use iHepatocytes2322 to analyse transcriptomics data obtained from patients with non-alcoholic fatty liver disease. We show that blood concentrations of chondroitin and heparan sulphates are suitable for diagnosing non-alcoholic steatohepatitis and for the staging of non-alcoholic fatty liver disease. Furthermore, we observe serine deficiency in patients with NASH and identify PSPH, SHMT1 and BCAT1 as potential therapeutic targets for the treatment of non-alcoholic steatohepatitis.
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              Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease.

              Cirrhosis and liver cancer are potential outcomes of advanced nonalcoholic fatty liver disease (NAFLD). It is not clear what factors determine whether patients will develop advanced or mild NAFLD, limiting noninvasive diagnosis and treatment before clinical sequelae emerge. We investigated whether DNA methylation profiles can distinguish patients with mild disease from those with advanced NAFLD, and how these patterns are functionally related to hepatic gene expression. We collected frozen liver biopsies and clinical data from patients with biopsy-proven NAFLD (56 in the discovery cohort and 34 in the replication cohort). Samples were divided into groups based on histologic severity of fibrosis: F0-1 (mild) and F3-4 (advanced). DNA methylation profiles were determined and coupled with gene expression data from the same biopsies; differential methylation was validated in subsets of the discovery and replication cohorts. We then analyzed interactions between the methylome and transcriptome. Clinical features did not differ between patients known to have mild or advanced fibrosis based on biopsy analysis. There were 69,247 differentially methylated CpG sites (76% hypomethylated, 24% hypermethylated) in patients with advanced vs mild NAFLD (P < .05). Methylation at fibroblast growth factor receptor 2, methionine adenosyl methyltransferase 1A, and caspase 1 was validated by bisulfite pyrosequencing and the findings were reproduced in the replication cohort. Methylation correlated with gene transcript levels for 7% of differentially methylated CpG sites, indicating that differential methylation contributes to differences in expression. In samples with advanced NAFLD, many tissue repair genes were hypomethylated and overexpressed, and genes in certain metabolic pathways, including 1-carbon metabolism, were hypermethylated and underexpressed. Functionally relevant differences in methylation can distinguish patients with advanced vs mild NAFLD. Altered methylation of genes that regulate processes such as steatohepatitis, fibrosis, and carcinogenesis indicate the role of DNA methylation in progression of NAFLD. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: Software
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                28 September 2018
                2018
                : 13
                : 9
                Affiliations
                [1 ] Division of Gastroenterology, Department of Medicine, Duke University Health System, Durham, NC, United States of America
                [2 ] Biostatistics and Bioinformatics, Duke University, Durham, NC, United States of America
                [3 ] Department of Obstetrics and Gynecology, Duke University Health System, Durham, NC, United States of America
                [4 ] Department of Medicine, Durham Veterans Affairs Health System, Durham, NC, United States of America
                Medizinische Fakultat der RWTH Aachen, GERMANY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Article
                PONE-D-18-16173
                10.1371/journal.pone.0204308
                6161885
                30265706

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                Page count
                Figures: 3, Tables: 4, Pages: 14
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: 5RC2-AA019399
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100006510, Duke University;
                Award ID: Florence McAlister Professor of Medicine Endowment Fund
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100007827, American College of Gastroenterology;
                Award ID: Junior Faculty Development Award
                Award Recipient :
                This work was supported by Florence McAlister Professor of Medicine Endowment Fund, National Institutes of Health 5RC2-AA019399 (PI: Diehl); American College of Gastroenterology Junior Faculty Development Award (2015; PI: Moylan). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Genetics
                Gene Expression
                Biology and life sciences
                Cell biology
                Chromosome biology
                Chromatin
                Chromatin modification
                DNA methylation
                Biology and life sciences
                Genetics
                Epigenetics
                Chromatin
                Chromatin modification
                DNA methylation
                Biology and life sciences
                Genetics
                Gene expression
                Chromatin
                Chromatin modification
                DNA methylation
                Biology and life sciences
                Genetics
                DNA
                DNA modification
                DNA methylation
                Biology and life sciences
                Biochemistry
                Nucleic acids
                DNA
                DNA modification
                DNA methylation
                Biology and life sciences
                Genetics
                Epigenetics
                DNA modification
                DNA methylation
                Biology and life sciences
                Genetics
                Gene expression
                DNA modification
                DNA methylation
                Biology and Life Sciences
                Developmental Biology
                Fibrosis
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Fatty Liver
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Biopsy
                Medicine and Health Sciences
                Health Care
                Health Care Policy
                Treatment Guidelines
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Cirrhosis
                Custom metadata
                Gene expression and methylation data are available through GEO at GSE31803. Clinical data will be made available after acceptance through the Duke NAFLD Biorepository for researchers who meet the criteria for access to confidential data.

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