Serum aminotransferases in nonalcoholic fatty liver disease are a signature of liver metabolic perturbations at the amino acid and Krebs cycle level

GUSTAVO O CASTAÑO; HERNÁN DOPAZO; JULIO SAN MARTINO; CARLOS J PIROLA; SILVIA SOOKOIAN; TOMAS FERNÁNDEZ GIANOTTI; GRACIELA GAJ; DIEGO FLICHMAN; ROMINA SCIAN; CRISTIAN ROHR; INA SEVIC

AMERICAN JOURNAL OF CLINICAL NUTRITION

AMER SOC CLINICAL NUTRITION

Lugar: Maryland, EE.UU.; Año: 2016

0002-9165

Background: Extensive epidemiologic studies have shown that cardiovasculardisease and the metabolic syndrome (MetS) are associatedwith serum concentrations of liver enzymes; however, fundamentalcharacteristics of this relation are currently unknown.Objective: We aimed to explore the role of liver aminotransferasesin nonalcoholic fatty liver disease (NAFLD) and MetS.Design: Liver gene- and protein-expression changes of aminotransferases,including their corresponding isoforms, were evaluated ina case-control study of patients with NAFLD (n = 42), which wasproven through a biopsy (control subjects: n = 10). We also carriedout a serum targeted metabolite profiling to the glycolysis, gluconeogenesis,and Krebs cycle (n = 48) and an exploration by thenext-generation sequencing of aminotransferase genes (n = 96).An in vitro study to provide a biological explanation of changesin the transcriptional level and enzymatic activity of aminotransferaseswas included.Results: Fatty liver was associated with a deregulated liver expressionof aminotransferases, which was unrelated to the disease severity. Metaboliteprofiling showed that serum aminotransferase concentrationsare a signature of liver metabolic perturbations, particularly at theamino acid metabolism and Krebs cycle level. A significant and positiveassociation between systolic hypertension and liver expressionlevels of glutamic-oxaloacetic transaminase 2 (GOT2) messengerRNA (Spearman R = 0.42, P = 0.03) was observed. The rs6993 locatedin the 3# untranslated region of the GOT2 locus was significantlyassociated with features of the MetS, including arterial hypertension[P = 0.028; OR: 2.285 (95% CI: 1.024, 5.09); adjusted by NAFLDseverity] and plasma lipid concentrations.Conclusions: In the context of an abnormal hepatic triglycerideaccumulation, circulating aminotransferases rise as a consequenceof the need for increased reactions of transamination to cope withthe liver metabolic derangement that is associated with greater gluconeogenesisand insulin resistance. Hence, to maintain homeostasis,the liver upregulates these enzymes, leading to changes in the amountsof amino acids released into the circulation.