Takeuchi M, Sakasai-Sakai A, Takata T, Ueda T, Takino J, Tsutsumi M, Hyogo H, Yamagishi S
Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan.
Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan.
Med Hypotheses. 2015 May;84(5):490-3. doi: 10.1016/j.mehy.2015.02.002. Epub 2015 Feb 10.
Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), leads to fibrosis and potentially cirrhosis, liver failure, and hepatocellular carcinoma, and is one of the most common causes of liver disease worldwide. NAFLD has also been implicated in other medical conditions such as insulin resistance, obesity, metabolic syndrome, hyperlipemia, hypertension, cardiovascular disease, and diabetes. Continuous hyperglycemia has been implicated in the pathogenesis of diabetic micro- and macro-vascular complications via various metabolic pathways, and numerous hyperglycemia-induced metabolic and hemodynamic conditions exist, including the increased generation of various types of advanced glycation end-products (AGEs). We recently demonstrated that glyceraldehyde-derived AGEs (Glycer-AGEs), the predominant components of toxic AGEs (TAGE), played an important role in the pathogenesis of angiopathy in diabetic patients. Moreover, a growing body of evidence suggests that the interaction between TAGE and the receptor for AGEs may alter intracellular signaling, gene expression, and the release of pro-inflammatory molecules and also elicits the generation of oxidative stress in numerous types of cells including hepatocytes and hepatic stellate cells. Serum levels of TAGE were significantly higher in NASH patients than in those with simple steatosis and healthy controls. Moreover, serum levels of TAGE inversely correlated with adiponectin (adiponectin is produced by adipose tissue and is an anti-inflammatory adipokine that can increase insulin sensitivity). Furthermore, immunohistochemical staining of TAGE showed intense staining in the livers of patients with NASH. Serum levels of TAGE may be a useful biomarker for discriminating NASH from simple steatosis. The administration of atorvastatin (10 mg daily) for 12 months significantly improved NASH-related metabolic parameters and significantly decreased serum levels of TAGE. The steatosis grade and NAFLD activity score were also significantly improved. These results demonstrated that atorvastatin decreased the serum levels of TAGE in NASH patients with dyslipidemia and suggest the usefulness of TAGE as a biomarker for the attenuation of NASH. Serum levels of TAGE were significantly higher in non-B or non-C hepatocellular carcinoma (NBNC-HCC) patients than in NASH subjects without HCC or control subjects. TAGE may be involved in the pathogenesis of NBNC-HCC, and could, therefore, be a biomarker that could discriminate NBNC-HCC from NASH. We propose that serum levels of TAGE are promising novel targets for the diagnosis of and therapeutic interventions against NASH.
非酒精性脂肪性肝病（NAFLD）范围从单纯性脂肪变性到非酒精性脂肪性肝炎（NASH），可导致肝纤维化，并可能发展为肝硬化、肝衰竭和肝细胞癌，是全球最常见的肝脏疾病病因之一。NAFLD还与其他病症有关，如胰岛素抵抗、肥胖、代谢综合征、高脂血症、高血压、心血管疾病和糖尿病。持续高血糖通过各种代谢途径参与糖尿病微血管和大血管并发症的发病机制，并且存在许多高血糖诱导的代谢和血流动力学状况，包括各种类型晚期糖基化终产物（AGEs）生成增加。我们最近证明，甘油醛衍生的AGEs（Glycer-AGEs）是毒性AGEs（TAGE）的主要成分，在糖尿病患者血管病变的发病机制中起重要作用。此外，越来越多的证据表明，TAGE与AGEs受体之间的相互作用可能会改变细胞内信号传导、基因表达以及促炎分子的释放，还会在包括肝细胞和肝星状细胞在内的多种类型细胞中引发氧化应激。NASH患者血清中TAGE水平显著高于单纯性脂肪变性患者和健康对照者。此外，TAGE血清水平与脂联素呈负相关（脂联素由脂肪组织产生，是一种抗炎性脂肪因子，可提高胰岛素敏感性）。此外，TAGE的免疫组织化学染色显示NASH患者肝脏中有强烈染色。TAGE血清水平可能是区分NASH与单纯性脂肪变性的有用生物标志物。给予阿托伐他汀（每日10mg）12个月可显著改善NASH相关的代谢参数，并显著降低TAGE血清水平。脂肪变性分级和NAFLD活动评分也显著改善。这些结果表明，阿托伐他汀可降低血脂异常的NASH患者的TAGE血清水平，并提示TAGE作为NASH缓解生物标志物的有用性。非B或非C型肝细胞癌（NBNC-HCC）患者血清TAGE水平显著高于无HCC 的NASH受试者或对照受试者。TAGE可能参与NBNC-HCC的发病机制，因此可能是区分NBNC-HCC与NASH的生物标志物。我们认为，TAGE血清水平有望成为NASH诊断和治疗干预的新靶点。
