Silvia Sookoian1, Gustavo O Castaño2, Romina Scian3, Tomas Fernández Gianotti4, Hernán Dopazo5, Cristian Rohr5, Graciela Gaj6, Julio San Martino6, Ina Sevic7, Diego Flichman7, Carlos J Pirola8. 1. Departments of Clinical and Molecular Hepatology and sookoian.silvia@lanari.fmed.uba.ar pirola.carlos@lanari.fmed.uba.ar. 2. Liver Unit, Medicine and Surgery Department, Hospital Abel Zubizarreta, Autonomous City of Buenos Aires, Argentina; and. 3. Departments of Clinical and Molecular Hepatology and Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-Instituto de Investigaciones Medicas. 4. Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-Instituto de Investigaciones Medicas. 5. Biomedical Genomics and Evolution Laboratory, Ecology, Genetics and Evolution Department, Faculty of Science, Instituto de Ecología, Genética y Evolución de Buenos Aires, and. 6. Department of Pathology, Hospital Diego Thompson, Buenos Aires, Argentina. 7. Department of Virology, School of Pharmacy and Biochemistry, University of Buenos Aires-National Scientific and Technical Research Council, Autonomous City of Buenos Aires, Argentina; 8. 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.
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. DESIGN: 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.
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. DESIGN: 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: Elena Larrieta-Carrasco; Yvonne N Flores; Luis R Macías-Kauffer; Paula Ramírez-Palacios; Manuel Quiterio; Eric G Ramírez-Salazar; Paola León-Mimila; Berenice Rivera-Paredez; Guillermo Cabrera-Álvarez; Samuel Canizales-Quinteros; Zuo-Feng Zhang; Tania V López-Pérez; Jorge Salmerón; Rafael Velázquez-Cruz Journal: Exp Mol Pathol Date: 2018-01-04 Impact factor: 3.362
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