Proteome Dynamics Reveals Pro-Inflammatory Remodeling of Plasma Proteome in a Mouse Model of NAFLD.
Proteome Dynamics Reveals Pro-Inflammatory Remodeling of Plasma Proteome in a Mouse Model of NAFLD.
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DOI：
10.1021/acs.jproteome.6b00601
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发表时间：
2016-09-02
影响因子：
4.4
通讯作者：
Kasumov T
中科院分区：
文献类型：
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作者：
Li L;Bebek G;Previs SF;Smith JD;Sadygov RG;McCullough AJ;Willard B;Kasumov T
非酒精性脂肪肝（NAFLD）与心血管疾病风险增加有关。由于肝脏是循环蛋白的主要来源，因此肝病可能导致血浆蛋白质组的改变并不奇怪，这与动脉粥样硬化有关。目前的研究使用低密度脂蛋白受体缺陷（LDLR−/−）小鼠来检查西方饮食（WD）诱导的NAFLD对血浆蛋白质组稳态的影响。使用2 H2O-代谢标记方法，我们发现，WD导致了在apoB耗尽血浆中分析的循环蛋白的促炎性分布，这是由于生产增加。与应激反应、脂质代谢和转运功能有关的短寿命蛋白的更新率随WD的增加而显著增加（P < 0.05）。通路分析显示，血浆蛋白质组动力学的改变与肝脏PPARα的抑制有关，这一点基于饲喂WD的小鼠中PPARα的基因和蛋白表达降低而得到证实。这些变化与apoB耗尽血浆的促炎性特性增加约4倍（P < 0.0001）相关。总之，蛋白质组动力学方法揭示了与肝脏疾病相关的血浆蛋白质组的促炎性重塑。本文使用的方法可以提供体内肝功能的有用度量，并且更好地使得能够研究围绕NAFLD和其他疾病的新疗法。
Nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular disease. Because the liver is the major source of circulatory proteins, it is not surprising that hepatic disease could lead to alterations in the plasma proteome, which are therein implicated in atherosclerosis. The current study used low-density lipoprotein receptor-deficient (LDLR−/−) mice to examine the impact of Western diet (WD)-induced NAFLD on plasma proteome homeostasis. Using a 2H2O-metabolic labeling method, we found that a WD led to a proinflammatory distribution of circulatory proteins analyzed in apoB-depleted plasma, which was attributed to an increased production. The fractional turnover rates of short-lived proteins that are implicated in stress-response, lipid metabolism, and transport functions were significantly increased with WD (P < 0.05). Pathway analyses revealed that alterations in plasma proteome dynamics were related to the suppression of hepatic PPARα, which was confirmed based on reduced gene and protein expression of PPARα in mice fed a WD. These changes were associated with ~4-fold increase (P < 0.0001) in the proinflammatory property of apoB-depleted plasma. In conclusion, the proteome dynamics method reveals proinflammatory remodeling of the plasma proteome relevant to liver disease. The approach used herein may provide a useful metric of in vivo liver function and better enable studies of novel therapies surrounding NAFLD and other diseases.