Shubham K, Vinay L, Vinod P K
Centre for Computational Natural Sciences and Bioinformatics, International Institute of Information Technology, Hyderabad-500032, India.
Mol Biosyst. 2017 Aug 22;13(9):1898-1911. doi: 10.1039/c7mb00013h.
Non-Alcoholic Fatty Liver Disease (NAFLD) is a complex spectrum of diseases ranging from simple steatosis to Non-Alcoholic Steatohepatitis (NASH) with fibrosis, which can progress to cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is complex, involving crosstalk between multiple organs, cell-types, and environmental and genetic factors. Dysfunction of the adipose tissue plays a central role in NAFLD progression. Here, we analysed transcriptomics data obtained from the Visceral Adipose Tissue (VAT) of NAFLD patients to understand how the VAT metabolism is altered at the genome scale and co-regulated with other cellular processes during the progression from obesity to NASH with fibrosis. For this purpose, we performed Weighted Gene Co-expression Network Analysis (WGCNA), a method that organizes the disease transcriptome into functional modules of cellular processes and pathways. Our analysis revealed the coordination of metabolic and inflammatory modules (termed "immunometabolism") in the VAT of NAFLD patients. We found that genes of arachidonic acid, sphingolipid and glycosphingolipid metabolism were upregulated and co-expressed with genes of proinflammatory signalling pathways and hypoxia in NASH/NASH with fibrosis. We hypothesize that these metabolic alterations might play a role in sustaining VAT inflammation. Furthermore, immunometabolism related genes were also co-expressed with genes involved in Extracellular Matrix (ECM) degradation. Our analysis indicates that upregulation of both ECM degrading enzymes and their inhibitors (incoherent feedforward loop) potentially leads to the ECM deposition in the VAT of NASH with fibrosis patients.
非酒精性脂肪性肝病（NAFLD）是一系列复杂的疾病，范围从单纯性脂肪变性到伴有纤维化的非酒精性脂肪性肝炎（NASH），后者可进展为肝硬化和肝细胞癌。NAFLD的发病机制复杂，涉及多个器官、细胞类型以及环境和遗传因素之间的相互作用。脂肪组织功能障碍在NAFLD进展中起核心作用。在此，我们分析了从NAFLD患者的内脏脂肪组织（VAT）获得的转录组学数据，以了解在从肥胖到伴有纤维化的NASH的进展过程中，VAT代谢在基因组水平上是如何改变的，以及如何与其他细胞过程共同调节。为此，我们进行了加权基因共表达网络分析（WGCNA），这是一种将疾病转录组组织成细胞过程和通路功能模块的方法。我们的分析揭示了NAFLD患者VAT中代谢和炎症模块（称为“免疫代谢”）的协调作用。我们发现，在NASH/伴有纤维化的NASH中，花生四烯酸、鞘脂和糖鞘脂代谢相关基因上调，并与促炎信号通路和缺氧相关基因共表达。我们推测这些代谢改变可能在维持VAT炎症中起作用。此外，免疫代谢相关基因也与参与细胞外基质（ECM）降解的基因共表达。我们的分析表明，ECM降解酶及其抑制剂的上调（非相干前馈环）可能导致伴有纤维化的NASH患者VAT中的ECM沉积。
