XBP-1s Is Linked to Suppressed Gluconeogenesis in the Ebb Phase of Burn Injury

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-1target 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.

[1]  L. Carbone.  Pain management standards in the eighth edition of the Guide for the Care and Use of Laboratory Animals. , 2012, Journal of the American Association for Laboratory Animal Science : JAALAS.

[2]  D. Moore,et al.  Endoplasmic reticulum stress and glucose homeostasis , 2011, Current opinion in clinical nutrition and metabolic care.

[3]  M. White,et al.  Regulation of glucose homeostasis through a XBP-1–FoxO1 interaction , 2011, Nature Medicine.

[4]  D. Herndon,et al.  Insulin Protects against Hepatic Damage Postburn , 2011, Molecular medicine.

[5]  D. Herndon,et al.  POST-BURN HEPATIC INSULIN RESISTANCE IS ASSOCIATED WITH ENDOPLASMIC RETICULUM (ER) STRESS , 2010, Shock.

[6]  In-kyu Lee,et al.  Endoplasmic reticulum stress-induced activation of activating transcription factor 6 decreases cAMP-stimulated hepatic gluconeogenesis via inhibition of CREB. , 2010, Endocrinology.

[7]  S. V. Cromphaut,et al.  Hyperglycaemia as part of the stress response: the underlying mechanisms. , 2009 .

[8]  D. Herndon,et al.  The hypermetabolic response to burn injury and interventions to modify this response. , 2009, Clinics in plastic surgery.

[9]  D. Herndon,et al.  Calcium and ER stress mediate hepatic apoptosis after burn injury , 2009, Journal of cellular and molecular medicine.

[10]  M. Montminy,et al.  The CREB Coactivator CRTC2 Links Hepatic ER Stress and Fasting Gluconeogenesis , 2009, Nature.

[11]  J. Mandl,et al.  Endoplasmic Reticulum: Nutrient Sensor in Physiology and Pathology , 2022 .

[12]  J. Yates,et al.  A Fasting Inducible Switch Modulates Gluconeogenesis Via Activator-Coactivator Exchange , 2008, Nature.

[13]  S. Dibo,et al.  Nutritional and pharmacological modulation of the metabolic response of severely burned patients: review of the literature (part 1). , 2008, Annals of burns and fire disasters.

[14]  P. Walter,et al.  Signal integration in the endoplasmic reticulum unfolded protein response , 2007, Nature Reviews Molecular Cell Biology.

[15]  X. Zhao-Fan,et al.  Insulin resistance following thermal injury: an animal study. , 2007, Burns : journal of the International Society for Burn Injuries.

[16]  R. Kaufman,et al.  From acute ER stress to physiological roles of the Unfolded Protein Response , 2006, Cell Death and Differentiation.

[17]  L. N. Valenti,et al.  Nuclear Trapping of the Forkhead Transcription Factor FoxO1 via Sirt-dependent Deacetylation Promotes Expression of Glucogenetic Genes* , 2005, Journal of Biological Chemistry.

[18]  L. Glimcher,et al.  Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes , 2004, Science.

[19]  Martin L. Yarmush,et al.  Expression profiling analysis of the metabolic and inflammatory changes following burn injury in rats. , 2004, Physiological genomics.

[20]  R. Tompkins,et al.  Support of the metabolic response to burn injury , 2004, The Lancet.

[21]  J. K. Oeser,et al.  Selective stimulation of G-6-Pase catalytic subunit but not G-6-P transporter gene expression by glucagon in vivo and cAMP in situ. , 2004, American journal of physiology. Endocrinology and metabolism.

[22]  D. Accili,et al.  Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice. , 2003, American journal of physiology. Endocrinology and metabolism.

[23]  Bruce M. Spiegelman,et al.  Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction , 2003, Nature.

[24]  K. Mori,et al.  XBP1 mRNA Is Induced by ATF6 and Spliced by IRE1 in Response to ER Stress to Produce a Highly Active Transcription Factor , 2001, Cell.

[25]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[26]  D. Accili,et al.  The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression. , 2001, The Journal of clinical investigation.

[27]  Guillaume Adelmant,et al.  Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1 , 2001, Nature.

[28]  T. Unterman,et al.  Gene- and Activation-specific Mechanisms for Insulin Inhibition of Basal and Glucocorticoid-induced Insulin-like Growth Factor Binding Protein-1 and Phosphoenolpyruvate Carboxykinase Transcription , 2001, The Journal of Biological Chemistry.

[29]  D. Massillon.  Regulation of the Glucose-6-phosphatase Gene by Glucose Occurs by Transcriptional and Post-transcriptional Mechanisms , 2001, The Journal of Biological Chemistry.

[30]  G. Stephanopoulos,et al.  Metabolic flux analysis of postburn hepatic hypermetabolism. , 2000, Metabolic engineering.

[31]  D. Accili,et al.  Insulin Stimulates Phosphorylation of the Forkhead Transcription Factor FKHR on Serine 253 through a Wortmannin-sensitive Pathway* , 1999, The Journal of Biological Chemistry.

[32]  J. K. Rose,et al.  Advances in the treatment of burn patients. , 1997, Burns : journal of the International Society for Burn Injuries.

[33]  J. Liu,et al.  Cyclic AMP induction of phosphoenolpyruvate carboxykinase (GTP) gene transcription is mediated by multiple promoter elements. , 1991, The Journal of biological chemistry.

[34]  C. Childs,et al.  Glucose metabolism in children during the first day after burn injury. , 1990, Archives of emergency medicine.

[35]  C. Tong,et al.  Hyperglycaemia after burn injury. , 1989, Burns : journal of the International Society for Burn Injuries.

[36]  R. Wolfe,et al.  Role of insulin and glucagon in the response of glucose and alanine kinetics in burn-injured patients. , 1986, The Journal of clinical investigation.

[37]  J. Peret,et al.  Comparison between starvation and consumption of a high protein diet: plasma insulin and glucagon and hepatic activities of gluconeogenic enzymes during the first 24 hours. , 1986, Diabete & metabolisme.

[38]  D. Wilmore,et al.  Combined Hormonal Infusion Simulates the Metabolic Response to Injury , 1984, Annals of surgery.

[39]  W. Lamers,et al.  cAMP stimulates transcription of the gene for cytosolic phosphoenolpyruvate carboxykinase in rat liver nuclei. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[40]  R. Wolfe,et al.  Glucose metabolism in severely burned patients. , 1979, Metabolism: clinical and experimental.

[41]  A. Mason,et al.  Development and analysis of a small animal model simulating the human postburn hypermetabolic response. , 1978, The Journal of surgical research.

[42]  R. Wolfe,et al.  Glucose and lactate kinetics in burn shock. , 1977, The American journal of physiology.

[43]  A. Mason,et al.  Catecholamines: Znediator of the Hypermetabolic Response to Thermal Injury , 1974, Annals of surgery.

[44]  S. V. Van Cromphaut.  Hyperglycaemia as part of the stress response: the underlying mechanisms. , 2009, Best practice & research. Clinical anaesthesiology.

[45]  S. Dibo,et al.  Nutritional and Pharmacological Modulation of the Metabolic Response of Severely Burned Patients: Review of the Literature (Part II)*. , 2008, Annals of burns and fire disasters.

[46]  D. Herndon,et al.  Altering metabolism. , 2005, The Journal of burn care & rehabilitation.

[47]  Jerry Donovan,et al.  Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. , 2003, Nature.

[48]  D. Cuthbertson.  The disturbance of metabolism produced by bony and non-bony injury, with notes on certain abnormal conditions of bone. , 1930, The Biochemical journal.