Diabetes of the Liver: The Link Between Nonalcoholic Fatty Liver Disease and HFCS-55
Diabetes of the Liver: The Link Between Nonalcoholic Fatty Liver Disease and HFCS-55
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DOI：
10.1038/oby.2009.58
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发表时间：
2009-11-01
期刊：
影响因子：
6.9
通讯作者：
Al-Mohanna, Futwan A.
中科院分区：
文献类型：
--
作者：
Collison, Kate S.;Saleh, Soad M.;Al-Mohanna, Futwan A.
非酒精性脂肪性肝病（NAFLD）与肥胖和胰岛素抵抗有关。它也是2型糖尿病的诱发因素。饮食因素被认为会导致这三种疾病。NAFLD的特点是肝内脂肪增加和线粒体功能障碍，其病因可能归因于过量的果糖摄入。在美国，高果糖玉米糖浆-55 （HFCS-55）的消费量高达平均每日总能量摄入的15%，与体重增加和肥胖有关。本研究的目的是通过检测HFCS-55对体外和体内肝细胞脂肪生成、胰岛素信号传导和细胞功能的影响，确定HFCS-55是否参与NAFLD的发病机制。肝细胞暴露于HFCS-55导致肝细胞甘油三酯（TG）和脂肪生成蛋白显著增加。活性氧代谢产物（ROM）的基础产量增加，同时对氧化挑战的反应能力下降。HFCS-55诱导胰岛素信号通路下调，如AKT1 （ser473）磷酸化减弱所示。与胰岛素抵抗密切相关的c-Jun氨基末端激酶（JNK）也被激活；并伴有内质网（ER）应激和细胞内游离钙扰动的增加。暴露于HFCS-55的肝细胞表现出线粒体功能障碍，并将细胞色素C （CytC）释放到细胞质中。富含20% HFCS-55的饲料在体内诱导肝脏脂肪变性和线粒体破坏；伴有低脂联素血症和空腹血清胰岛素和视黄醇结合蛋白4 （RBP4）水平升高。综上所述，我们的研究结果表明HFCS-55可能参与NAFLD发病机制的潜在机制。
Nonalcoholic fatty liver disease (NAFLD) is associated with obesity and insulin resistance. It is also a predisposing factor for type 2 diabetes. Dietary factors are believed to contribute to all three diseases. NAFLD is characterized by increased intrahepatic fat and mitochondrial dysfunction, and its etiology may be attributed to excessive fructose intake. Consumption of high fructose corn syrup-55 (HFCS-55) stands at up to 15% of the average total daily energy intake in the United States, and is linked to weight gain and obesity. The aim of this study was to establish whether HFCS-55 could contribute to the pathogenesis of NAFLD, by examining the effects of HFCS-55 on hepatocyte lipogenesis, insulin signaling, and cellular function, in vitro and in vivo. Exposure of hepatocyles to HFCS-55 caused a significant increase in hepatocellular triglyceride (TG) and lipogenic proteins. Basal production of reactive oxygen metabolite (ROM) was increased, together with a decreased capacity to respond to an oxidative challenge. HFCS-55 induced a downregulation of the insulin signaling pathway, as indicated by attenuated (ser473)phosphorylation of AKT1. The c-Jun amino-terminal kinase (JNK), which is intimately linked to insulin resistance, was also activated; and this was accompanied by an increase in endoplasmic reticulum (ER) stress and intracellular free calcium perturbation. Hepatocytes exposed to HFCS-55 exhibited mitochondrial dysfunction and released cytochrome C (CytC) into the cytosol. Hepatic steatosis and mitochondrial disruption was induced in vivo by a diet enriched with 20% HFCS-55; accompanied by hypoadiponectinemia and elevated fasting serum insulin and retinol-binding protein-4 (RBP4) levels. Taken together our findings indicate a potential mechanism by which HFCS-55 may contribute to the pathogenesis of NAFLD.