Serum aminotransferases in nonalcoholic fatty liver disease are a signature of liver metabolic perturbations at the amino acid and Krebs cycle level
Serum aminotransferases in nonalcoholic fatty liver disease are a signature of liver metabolic perturbations at the amino acid and Krebs cycle level
复制标题
DOI：
10.3945/ajcn.115.118695
复制
发表时间：
2016-02-01
影响因子：
7.1
通讯作者：
Pirola, Carlos J.
中科院分区：
文献类型：
--
作者：
Sookoian, Silvia;Castano, Gustavo O.;Pirola, Carlos J.
背景资料：广泛的流行病学研究表明，心血管疾病和代谢综合征（MetS）与血清肝酶浓度相关;然而，这种关系的基本特征目前尚不清楚。目的：我们旨在探讨肝脏转氨酶在非酒精性脂肪性肝病（NAFLD）和代谢综合征中的作用。设计：在NAFLD患者（n = 42）的病例对照研究中评价了转氨酶（包括其相应的亚型）的肝脏基因和蛋白表达变化，通过活组织检查证实（对照受试者：n = 10）。我们还进行了糖酵解、异生和克雷布斯循环的血清靶向代谢物分析（n = 48），并通过下一代转氨酶基因测序进行了探索（n = 96）。一项体外研究，以提供一个生物学解释的转录水平和酶活性的变化aminotransferases increased.Results：脂肪肝与肝脏表达失调的aminotransferases，这是无关的疾病的严重程度。代谢物分析表明，血清转氨酶浓度是肝脏代谢紊乱的标志，特别是在氨基酸代谢和克雷布斯循环水平。收缩期高血压与肝脏谷草转氨酶2（GOT 2）mRNA表达水平显著正相关（斯皮尔曼R= 0.42，P = 0.03）。位于GOT 2基因3'端非翻译区的rs6993与MetS的特征（包括动脉高压）显著相关[P = 0.028; OR：2.285（95% CI：1.024，5.09）;根据NAFLD严重程度和血浆脂质浓度进行调整。在异常肝甘油三酯蓄积的情况下，循环转氨酶升高是由于需要增加的转氨反应以科普与更大的肝损伤相关的肝代谢紊乱。胰岛素抵抗的机制。因此，为了维持体内平衡，肝脏上调这些酶，导致释放到循环中的氨基酸量的变化。
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.