The Adaptive Endoplasmic Reticulum Stress Response to Lipotoxicity in Progressive Human Nonalcoholic Fatty Liver Disease
The Adaptive Endoplasmic Reticulum Stress Response to Lipotoxicity in Progressive Human Nonalcoholic Fatty Liver Disease
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DOI：
10.1093/toxsci/kft230
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发表时间：
2014-01-01
影响因子：
3.8
通讯作者：
Cherrington, Nathan J.
中科院分区：
文献类型：
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作者：
Lake, April D.;Novak, Petr;Cherrington, Nathan J.
非酒精性脂肪性肝病(NAFLD)可能会在7%-14%的美国人口中从简单的脂肪变性发展为严重的非酒精性脂肪性肝炎(NASH)，其形式为氧化应激和炎症增加。内质网(ER)应激信号和未折叠蛋白反应(UPR)是当高水平的脂质和错误折叠的蛋白质改变ER稳态时触发的，从而在NAFLD肝脏内创造了脂毒环境。本研究的目的是确定内质网应激相关基因在人类NAFLD进展阶段的协调调节。用单个Affymetrix基因芯片人1.0 ST芯片、免疫印迹和免疫组织化学方法分析了正常、脂肪变性、NASH(脂肪)和NASH(非脂肪)的人体肝脏样本。对自噬、细胞凋亡、脂肪生成和内质网应激/UPR基因类别进行基因集富集性分析。在NASH中观察到ER应激相关脂肪生成和ER应激/UPR基因类别中下调基因的丰富。相反，在NASH中观察到上调的ER应激相关基因用于自噬和凋亡基因类别的丰富。适应性肝反应蛋白STC2和转录因子X盒结合蛋白1剪接(XBP-1S)的蛋白表达在NASH样本中显著升高，而其他下游ER应激蛋白包括CHOP、ATF4和磷酸化的JNK和eIF2在疾病进展过程中没有明显变化。脂肪变性和NASH肝组织中XBP-1总蛋白的核积聚增加。这些发现揭示了人NAFLD对肝脏ER应激存在协调的、适应性的转录反应。
Nonalcoholic fatty liver disease (NAFLD) may progress from simple steatosis to severe, nonalcoholic steatohepatitis (NASH) in 7%14% of the U.S. population through a second hit in the form of increased oxidative stress and inflammation. Endoplasmic reticulum (ER) stress signaling and the unfolded protein response (UPR) are triggered when high levels of lipids and misfolded proteins alter ER homeostasis creating a lipotoxic environment within NAFLD livers. The objective of this study was to determine the coordinate regulation of ER stressassociated genes in the progressive stages of human NAFLD. Human liver samples categorized as normal, steatosis, NASH (Fatty), and NASH (Not Fatty) were analyzed by individual Affymetrix GeneChip Human 1.0 ST microarrays, immunoblots, and immunohistochemistry. A gene set enrichment analysis was performed on autophagy, apoptosis, lipogenesis, and ER stress/UPR gene categories. An enrichment of downregulated genes in the ER stressassociated lipogenesis and ER stress/UPR gene categories was observed in NASH. Conversely, an enrichment of upregulated ER stressassociated genes for autophagy and apoptosis gene categories was observed in NASH. Protein expression of the adaptive liver response protein STC2 and the transcription factor X-box binding protein 1 spliced (XBP-1s) were significantly elevated among NASH samples, whereas other downstream ER stress proteins including CHOP, ATF4, and phosphorylated JNK and eIF2 were not significantly changed in disease progression. Increased nuclear accumulation of total XBP-1 protein was observed in steatosis and NASH livers. The findings reveal the presence of a coordinated, adaptive transcriptional response to hepatic ER stress in human NAFLD.