A Global View on TMT-based Quantitative Proteomic Analysis of Rat Livers During Acute Hypoxia

Abstract Background: Acute hypoxia consistently results in altitude sickness and can be fatal. Until present, no studies focusing on global proteomic changes induced by acute hypoxia have been reported. Here, we combined animal experiments and tandem mass tag (TMT)-based proteomic analysis to identify metabolic changes as a result of acute hypoxia. Methods: We first generated a rat model under acute hypoxia conditions, and combined animal experiments and TMT-based proteomics to identify metabolic changes under acute hypoxia. Then we used qPCR analyses to validate the key regulators, and present a schematic model of acute reactions occurring in the livers of rats subjected to acute hypoxia challenge. Results: We identified a large number of acute hypoxic responsive proteins in diverse biological pathways, which helped unveil the different mechanisms involved in hypoxia responses in rats. These pathways included those of peroxisome, peroxisome proliferator-activated receptor (PPAR) signaling, lipid metabolism, glycolysis/gluconeogenesis, and amino acid metabolism. According to data obtained from proteomic analysis, rats were able to maintain normal physical activity as a response to acute hypoxia by activating their catabolic capacity in order to get more energy (e.g., lipolysis and amino acid catabolism), and decreasing biosynthesis to reduce energy consumption (e.g., biosynthesis of amino acids and lipids). Conclusions: We identified a large number of acute hypoxia-responsive proteins associated with diverse biological pathways, and showed rats quickly respond to acute hypoxia by activating lipid biosynthesis to increase lipid storage, and reducing lipolysis to reduce energy consumption. The observed hypoxia-related changes in the liver proteome of rats provide a deeper understanding on the mammalian response to hypoxia.