PCB126 Inhibits the Activation of AMPK-CREB Signal Transduction Required for Energy Sensing in Liver
Autor: | Fabian A Sandgruber, Benjamin A Elser, Katherine N. Gibson-Corley, Xueshu Li, Larry W. Robertson, Gopi S. Gadupudi |
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Rok vydání: | 2018 |
Předmět: |
Male
0301 basic medicine medicine.medical_specialty Glycogenolysis AMP-Activated Protein Kinases 010501 environmental sciences Carbohydrate metabolism Toxicology CREB 01 natural sciences Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Internal medicine medicine Animals Cyclic AMP Response Element-Binding Protein 0105 earth and related environmental sciences Glycogen biology Chemistry Gluconeogenesis AMPK Metabolism Pcb126 and Altered Signaled Transduction in Liver medicine.disease Polychlorinated Biphenyls Liver Glycogen Glucose 030104 developmental biology Endocrinology Liver biology.protein Steatosis Energy Metabolism Transcriptome Signal Transduction |
Zdroj: | Toxicological Sciences. 163:440-453 |
ISSN: | 1096-0929 1096-6080 |
Popis: | 3,3′,4,4′,5-pentachlorobiphenyl (PCB126), a dioxin-like PCB, elicits toxicity through a wide array of noncarcinogenic effects, including metabolic syndrome, wasting, and nonalcoholic fatty-liver disease. Previously, we reported decreases in the transcription of several enzymes involved in gluconeogenesis, before the early onset of lipid accumulation. Hence, this study was aimed at understanding the impact of resultant decreases gluconeogenic enzymes on growth, weight, and metabolism in the liver, upon extended exposure. Male Sprague Dawley rats (75–100 g), fed a defined AIN-93G diet, were injected (ip) with single dose of soy oil (5 ml/kg body weight; n = 14) or PCB126 (5 µmol/kg; n = 15), 28 days, prior euthanasia. A subset of rats from each group were fasted for 12 h (vehicle [n = 6] and PCB126 [n = 4]). Rats only showed significant weight loss between days 14 and 28 (p < .05) and some mortality (p = .0413). As in our previous studies, the expression levels of enzymes involved in gluconeogenesis (Pepck-c, G6Pase, Sds, Pc, and Ldh-A) and glycogenolysis (Pygl) were strongly downregulated. The decreased expression of these enzymes in PCB126-treated rats after a 12 h fast decreased hepatic glucose production from glycogen and gluconeogenic substrates, exacerbating the hypoglycemia. Additionally, PCB126 caused hepatic steatosis and decreased the expression of the transcription factor Pparα and its targets, necessary for fatty-acid oxidation. The observed metabolic disruption across multiple branches of fasting metabolism resulted from inhibition in the activation of enzyme AMPK and transcription factor CREB signaling, necessary for “sensing” energy-deprivation and the induction of enzymes that respond to the PCB126 triggered fuel crisis in liver. |
Databáze: | OpenAIRE |
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