Abstract
The first 24 h following burn injury is known as the ebb phase and is characterized by a depressed metabolic rate. While the postburn ebb phase has been well described, the molecular mechanisms underlying this response are poorly understood. The endoplasmic reticulum (ER) regulates metabolic rate by maintaining glucose homeostasis through the hepatic ER stress response. We have shown that burn injury leads to ER stress in the liver during the first 24 h following thermal injury. However, whether ER stress is linked to the metabolic responses during the ebb phase of burn injury is poorly understood. Here, we show in an animal model that burn induces activation of activating transcription factor 6 (ATF6) and inositol requiring enzyme-1 (IRE-1) and this leads to increased expression of spliced X-box binding protein-1 (XBP-1s) messenger ribonucleic acid (mRNA) during the ebb phase. This is associated with increased expression of XBP-1 target genes and downregulation of the key gluconeogenic enzyme glucose-6-phosphatase (G6Pase). We conclude that upregulation of the ER stress response after burn injury is linked to attenuated gluconeogenesis and sustained glucose tolerance in the postburn ebb phase.
Highlights
Maintaining blood glucose levels in the narrow range of 60 to140 mg/dL tightly regulates glucose metabolism in healthy individuals regardless of nutritional state [1]
In an animal burn model, we have shown that burn injury leads to an increase in hepatic endoplasmic reticulum (ER) stress within the first 24 h after thermal injury [25]
We considered the possibility that induction of the ER stress response is mechanistically linked to decreased metabolic rate during the ebb phase of burn injury
Summary
Maintaining blood glucose levels in the narrow range of 60 to140 mg/dL tightly regulates glucose metabolism in healthy individuals regardless of nutritional state [1] Severe traumas such as burn injury perturb glucose homeostasis by increasing abnormal energy substrate production and utilization [2]. The endoplasmic reticulum (ER) senses changes in nutrient supply by linking metabolic cues to cellular signaling mechanisms [16] An example of this signaling mechanism is initiation of the mammalian ER stress response pathway [17]. We considered the possibility that induction of the ER stress response is mechanistically linked to decreased metabolic rate during the ebb phase of burn injury. We show that ER stress-induced upregulation of XBP-1s is linked to attenuated gluconeogenesis and sustained glucose tolerance in the ebb phase postburn injury
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