Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA.
Purdue Proteomics Facility, Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907, USA; Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA..
J Proteomics. 2021 Feb 10;232:104072. doi: 10.1016/j.jprot.2020.104072. Epub 2020 Dec 10.
A metabolic consequence of obesity is hepatosteatosis, which can develop into more serious diseases in the non-alcoholic fatty liver disease (NAFLD) spectrum. The goal of this study was to identify the protein signature of liver in the postprandial state in obesity compared to leanness. The postprandial state is of interest due to the central role of the liver in regulating macronutrient and energy homeostasis during the fed-fast cycle and lack of previously reported controlled studies in the postprandial state. Therefore, we assessed the proteome and phosphoproteome of liver in the postprandial state from diet-induced obese (DIO) and lean mice using untargeted LC-MS/MS analysis. We identified significant alterations in the levels of proteins involved in fatty acid oxidation, activation, and transport, as well as proteins involved in energy metabolism including ketogenesis, tricarboxylic acid cycle, and electron transport chain in liver of DIO compared to lean mice. Additionally, phosphorylated proteins in liver of DIO and lean mice reflect possible regulatory mechanisms controlling fatty acid metabolism and gene expression that may contribute to hepatic metabolic alterations in obesity. Our data indicates PPARα-mediated transcriptional regulation of lipid metabolism and adaptation to hepatic lipid overload. The results of this study expand our knowledge of the molecular changes that occur in liver in the postprandial state in obesity compared to leanness. SIGNIFICANCE: Proteome and phosphoproteome studies of liver in a controlled postprandial state in obesity and leanness are lacking; however, this information is crucial to understanding how obesity-associated hepatosteatosis influences postprandial nutrient and energy metabolism. In this global shotgun proteome and phosphoproteome analysis, we identified unique protein signatures defining obesity and leanness in liver in the postprandial state and identified potential mechanisms contributing to hepatic metabolic alterations in obesity. The results of this study provide a foundation to focus future experiments on the contribution of altered protein and phosphorylation patterns to postprandial metabolism in obesity-associated hepatosteatosis.
肥胖的一个代谢后果是肝脂肪变性，它可以在非酒精性脂肪性肝病（NAFLD）谱中发展成更严重的疾病。本研究的目的是确定肥胖与消瘦时肝脏在餐后状态下的蛋白质特征。由于肝脏在fed-fast 循环中调节宏量营养素和能量稳态的核心作用，以及之前在餐后状态下没有报道过对照研究，因此餐后状态是很有研究意义的。因此，我们使用非靶向 LC-MS/MS 分析评估了饮食诱导肥胖（DIO）和瘦小鼠肝脏在餐后状态下的蛋白质组和磷酸蛋白质组。我们发现，与瘦小鼠相比，DIO 小鼠肝脏中参与脂肪酸氧化、激活和转运的蛋白质以及参与酮体生成、三羧酸循环和电子传递链等能量代谢的蛋白质的水平发生了显著变化。此外，DIO 和瘦小鼠肝脏中的磷酸化蛋白反映了可能控制脂肪酸代谢和基因表达的调节机制，这些机制可能有助于肥胖时肝脏的代谢改变。我们的数据表明，PPARα 介导的脂质代谢转录调控和对肝脏脂质过载的适应。本研究的结果扩展了我们对肥胖与消瘦时肝脏在餐后状态下发生的分子变化的认识。意义：缺乏对肥胖和消瘦时肝脏在对照餐后状态下的蛋白质组和磷酸蛋白质组的研究；然而，这些信息对于了解肥胖相关的肝脂肪变性如何影响餐后营养和能量代谢是至关重要的。在这项全蛋白质组和磷酸蛋白质组的分析中，我们确定了定义肥胖和消瘦时肝脏在餐后状态下的独特蛋白质特征，并确定了潜在的机制，这些机制可能导致肥胖时肝脏代谢的改变。本研究的结果为未来的实验提供了一个基础，重点研究改变的蛋白质和磷酸化模式对肥胖相关肝脂肪变性中餐后代谢的贡献。
