title: Serum aminotransferases in nonalcoholic fatty liver disease are a signature of liver metabolic perturbations at the amino acid and Krebs cycle level.
abstract: BACKGROUND
  Extensive epidemiologic studies have shown that cardiovascular disease and the metabolic syndrome (MetS) are associated with serum concentrations of liver enzymes; however, fundamental characteristics of this relation are currently unknown.
  
  
  OBJECTIVE
  We aimed to explore the role of liver aminotransferases in nonalcoholic fatty liver disease (NAFLD) and MetS.
  
  
  METHODS
  Liver gene- and protein-expression changes of aminotransferases, including their corresponding isoforms, were evaluated in a case-control study of patients with NAFLD (n = 42), which was proven through a biopsy (control subjects: n = 10). We also carried out a serum targeted metabolite profiling to the glycolysis, gluconeogenesis, and Krebs cycle (n = 48) and an exploration by the next-generation sequencing of aminotransferase genes (n = 96). An in vitro study to provide a biological explanation of changes in the transcriptional level and enzymatic activity of aminotransferases was included.
  
  
  RESULTS
  Fatty liver was associated with a deregulated liver expression of aminotransferases, which was unrelated to the disease severity. Metabolite profiling showed that serum aminotransferase concentrations are a signature of liver metabolic perturbations, particularly at the amino acid metabolism and Krebs cycle level. A significant and positive association between systolic hypertension and liver expression levels of glutamic-oxaloacetic transaminase 2 (GOT2) messenger RNA (Spearman R = 0.42, P = 0.03) was observed. The rs6993 located in the 3' untranslated region of the GOT2 locus was significantly associated with features of the MetS, including arterial hypertension [P = 0.028; OR: 2.285 (95% CI: 1.024, 5.09); adjusted by NAFLD severity] and plasma lipid concentrations.
  
  
  CONCLUSIONS
  In the context of an abnormal hepatic triglyceride accumulation, circulating aminotransferases rise as a consequence of the need for increased reactions of transamination to cope with the liver metabolic derangement that is associated with greater gluconeogenesis and insulin resistance. Hence, to maintain homeostasis, the liver upregulates these enzymes, leading to changes in the amounts of amino acids released into the circulation.
authors.affiliation: Departments of Clinical and Molecular Hepatology and sookoian.silvia@lanari.fmed.uba.ar pirola.carlos@lanari.fmed.uba.ar.
authors.forename: Silvia
authors.identifier: http://orcid.org/0000-0001-5929-5470
authors.initials: S
authors.lastname: Sookoian
authors.affiliation: Liver Unit, Medicine and Surgery Department, Hospital Abel Zubizarreta, Autonomous City of Buenos Aires, Argentina; and.
authors.forename: Gustavo O
authors.initials: GO
authors.lastname: Castaño
authors.affiliation: Departments of Clinical and Molecular Hepatology and Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-Instituto de Investigaciones Medicas.
authors.forename: Romina
authors.initials: R
authors.lastname: Scian
authors.affiliation: Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-Instituto de Investigaciones Medicas.
authors.forename: Tomas
authors.initials: T
authors.lastname: Fernández Gianotti
authors.affiliation: Biomedical Genomics and Evolution Laboratory, Ecology, Genetics and Evolution Department, Faculty of Science, Instituto de Ecología, Genética y Evolución de Buenos Aires, and.
authors.forename: Hernán
authors.initials: H
authors.lastname: Dopazo
authors.affiliation: Biomedical Genomics and Evolution Laboratory, Ecology, Genetics and Evolution Department, Faculty of Science, Instituto de Ecología, Genética y Evolución de Buenos Aires, and.
authors.forename: Cristian
authors.initials: C
authors.lastname: Rohr
authors.affiliation: Department of Pathology, Hospital Diego Thompson, Buenos Aires, Argentina.
authors.forename: Graciela
authors.initials: G
authors.lastname: Gaj
authors.affiliation: Department of Pathology, Hospital Diego Thompson, Buenos Aires, Argentina.
authors.forename: Julio
authors.initials: J
authors.lastname: San Martino
authors.affiliation: Department of Virology, School of Pharmacy and Biochemistry, University of Buenos Aires-National Scientific and Technical Research Council, Autonomous City of Buenos Aires, Argentina;
authors.forename: Ina
authors.initials: I
authors.lastname: Sevic
authors.affiliation: Department of Virology, School of Pharmacy and Biochemistry, University of Buenos Aires-National Scientific and Technical Research Council, Autonomous City of Buenos Aires, Argentina;
authors.forename: Diego
authors.initials: D
authors.lastname: Flichman
authors.affiliation: Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-Instituto de Investigaciones Medicas, sookoian.silvia@lanari.fmed.uba.ar pirola.carlos@lanari.fmed.uba.ar.
authors.forename: Carlos J
authors.identifier: http://orcid.org/0000-0001-8234-4058
authors.initials: CJ
authors.lastname: Pirola
mesh_terms: D000410:Alanine Transaminase / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism; D024443:Aspartate Aminotransferase, Cytoplasmic / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D024442:Aspartate Aminotransferase, Mitochondrial / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D004790:Enzyme Induction; D005234:Fatty Liver / Q000209:etiology; D005260:Female; D005943:Gluconeogenesis; D006801:Humans; D007333:Insulin Resistance; D007527:Isoenzymes / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide
chemical_list: D000596:Amino Acids; D015415:Biomarkers; D007527:Isoenzymes; D024443:Aspartate Aminotransferase, Cytoplasmic; D024442:Aspartate Aminotransferase, Mitochondrial; D000410:Alanine Transaminase
keywords: fatty liver; gene expression; liver injury; metabolomics; transaminases