Integrative transcriptomic analysis of NAFLD animal model reveals dysregulated genes and pathways in metabolism
Integrative transcriptomic analysis of NAFLD animal model reveals dysregulated genes and pathways in metabolism
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NAFLD 动物模型的综合转录组分析揭示了代谢失调的基因和途径
DOI：
10.1016/j.gene.2016.09.047
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发表时间：
2016
期刊：
影响因子：
3.5
通讯作者：
Yang Li
中科院分区：
文献类型：
--
作者：
Yang Wenhui;He Yan;Liu Shijie;Gan Lulu;Zhang Zhiguo;Wang Jun;Liang Jie;Dong Yang;Wang Qing;Hou Zongliu;Yang Li
肝细胞中代谢的失调导致肝脏疾病，例如肝炎和非酒精性脂肪性肝病（NAFLD）。NAFLD代表从单纯性脂肪变性到非酒精性脂肪性肝炎（NASH）的一系列肝脏疾病。NASH很可能进展为肝硬化、肝功能衰竭和肝细胞癌，导致长期预后不良。然而，NAFLD发展的确切机制尚未得到很好的阐明。为了更好地了解NAFLD的发病机制，我们从转录组的全局角度对NAFLD大鼠模型的肝脏进行了综合分析。通过系统和综合分析，我们发现高脂饲料喂养可引起转运、血管生成和细胞粘附的上调，这可能导致大量游离脂肪酸转运、肝纤维化和肝细胞损伤。GO树分析显示血管生成上调。GO术语是对高脂肪饮食的反应，高脂肪饮食可能导致纤维化。通路相互作用网络表明，上调“缬氨酸，亮氨酸和异亮氨酸代谢”可能会降低支链氨基酸（BCAA）的血清浓度。BCAA在NAFLD动物模型中降解增强，可能导致肝细胞再生抑制、白蛋白生成减少、肝癌抑制减弱、免疫力下降。总体而言，高脂饮食上调了多种代谢，这些代谢在TCA循环中会聚。高脂血症使肝线粒体处于“忙碌状态”。综合而言，参与生物学过程和代谢失调的基因可以作为评估NAFLD进展和治疗靶点的指标。
Dysregulation of metabolism in hepatocytes leads to hepatic diseases such as hepatitis and non-alcoholic fatty liver disease (NAFLD). NAFLD represents a spectrum of liver diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). NASH is likely to progress to cirrhosis, liver failure and hepatocellular carcinoma, which lead to poor long-term prognosis. However, the exact mechanism of development of NAFLD is not well elucidated. In order to better understand the pathogenesis of NAFLD, we have performed an integrative analysis to livers from NAFLD rat models in a global view of the transcriptome. By systemic and integrative analyses, we have found that transport, angiogenesis and cell adhesion were upregulated in response to high fat diet feeding, which may cause a large amount of free fatty acid transport, hepatic fibrosis and hepatocytes injury. GO tree analysis has shown that angiogenesis was upregulated. GO term in response to high fat diet which may cause fibrosis. The pathway interaction network has indicated that upregulated “valine, leucine, and isoleucine metabolism” may decrease the serum concentration of branched-chain amino acid (BCAA). The enhanced degradation of BCAA in NAFLD animal models may lead to inhibition of the regeneration of hepatocytes, reducing the production of albumin, attenuating the inhibition of liver cancer and decreasing immunity. Overall, high fat diet upregulated a variety of metabolism which have converged at TCA cycle. High fatty has pushed the hepatic mitochondria to a “busy state”. Comprehensively, genes participated in dysregulated biological process and metabolisms may be served as indicators for evaluation of NAFLD progression and therapeutic targets.