Gadupudi GS, Klaren WD, Olivier AK, Klingelhutz AJ, Robertson LW. Diminished phosphorylation of CREB Is a key event in the dysregulation of gluconeogenesis, glycogenolysis and fatty acid oxidation in PCB126 hepatotoxicity. Chem Res Toxicol 29(9):1504–1509. DOI: 10.1021/acs.chemrestox.6b00172.
The dioxin-like PCB126 elicits toxicity in various target organs. In rat liver, an alteration in the transcript levels of several genes involved in glucose and fatty acid metabolism provides insights into the origin of its hepatotoxicity. To explore the mechanisms, male Sprague-Dawley rats, fed an AIN-93G diet, were injected with PCB126 (1 or 5 μmol/kg) or corn oil and euthanized after 2 weeks. PCB126 significantly decreased serum glucose levels and the transcript levels of genes of many gluconeogenic and glycogenolytic enzymes under the transcriptional control of a nuclear transcription factor, cAMP response element-binding protein (CREB). As a novel finding, we show that PCB126 significantly decreases CREB phosphorylation, which is important for regulating both gluconeogenesis and fatty acid oxidation in the liver and explains CREB’s integrative effects on both carbohydrate and lipid metabolism in PCB126 toxicity.