Differential Proteomic Analysis of STAT6 Knockout Mice Reveals New Regulatory Function in Liver Lipid Homeostasis
Differential Proteomic Analysis of STAT6 Knockout Mice Reveals New Regulatory Function in Liver Lipid Homeostasis
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DOI：
10.1021/pr9003272
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发表时间：
2009-10-01
影响因子：
4.4
通讯作者：
Szanto, Ildiko
中科院分区：
文献类型：
--
作者：
Iff, Joel;Wang, Wei;Szanto, Ildiko
增加的炎症信号传导是代谢紊乱的关键特征。在这种情况下，增加的促炎信号的作用已被广泛研究。相比之下，没有努力致力于研究相反的情况：抗炎信号的衰减及其在代谢稳态中的作用。IL-4和IL-13是通过信号转导和转录激活因子6（STAT 6）进行信号传导的抗炎细胞因子。我们的研究旨在评估STAT 6信号转导的缺乏对肝脏稳态的影响。为此，我们使用2D纳米LC-MS/MS和iTRAQ标记技术分析了野生型和STAT 6敲除小鼠的肝脏蛋白质组。通过定量蛋白质组分析确定的蛋白质的协调变化表明脂质稳态紊乱和肝细胞应激状态。最重要的是，在基因敲除小鼠中，肝脏脂肪酸结合蛋白（FABP 1）的表达增加。与升高的FABP 1表达一致，我们在STAT 6缺陷小鼠中发现了潜在的肝脏脂质积累，当小鼠被高脂肪饮食攻击时，这种积累进一步加剧。总之，我们的研究揭示了迄今为止STAT 6在调节肝脏脂质稳态中的未表征作用，并证明了抗炎信号在防御肝脏脂肪变性发展中的重要性。
Increased inflammatory signaling is a key feature of metabolic disorders. In this context, the role of increased pro-inflammatory signals has been extensively studied. By contrast, no efforts have been dedicated to study the contrasting scenario: the attenuation of anti-inflammatory signals and their role in metabolic homeostasis. IL-4 and IL-13 are anti-inflammatory cytokines signaling through the Signal Transducer and Activator of Transcription 6 (STAT6). Our study was aimed at evaluating the lack of STAT6 signaling on liver homeostasis. To this end we analyzed the liver proteome of wild type and STAT6 knock-out mice using 2D nanoscale LC-MS/MS with iTRAQ labeling technique. The coordinated changes in proteins identified by this quantitative proteome analysis indicated disturbed lipid homeostasis and a state of hepatocellular stress. Most significantly, the expression of the liver fatty acid binding protein (FABP1) was increased in the knock-out mice. In line with the elevated FABP1 expression we found latent liver lipid accumulation in the STAT6-deficient mice which was further aggravated when mice were challenged by a high fat diet. In conclusion, our study revealed a so far uncharacterized role for STAT6 in regulating liver lipid homeostasis and demonstrates the importance of anti-inflammatory signaling in the defense against the development of liver steatosis.