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. Society of Toxicology Annual Meeting, Baltimore, Md, and NIEHS Environmental Health Science FEST, Durham, NC, 2017.
3,3’,4,4’,5-pentachlorobiphenyl (PCB126), a aryl hydrocarbon receptor (AhR) agonist, is strongly associated with metabolic disorders such as diabetes and nonalcoholic fatty liver disease (NAFLD) in humans. However the underlying mechanisms are not clear. We hypothesized that PCB126 disrupts carbohydrate and lipid metabolism in the liver, leading to altered energy homeostasis. Separate animal studies were performed using a rat model to characterize the time- and dose-dependent metabolic disruption after PCB126 administration. The chronology of PCB126 toxicity showed early decreases in serum glucose levels at 9 h, that worsened in a time-dependent way until the end of the study at 12 d. Lipid accumulation increased, between 3 d and 12 d of exposure to PCB126, worsening the hepatic steatosis. The observed fatty liver was also found to be dose-dependently aggravated at 1 and 5 µmol/Kg of PCB126 exposure. The decrease in serum glucose results from decreases in the transcript levels of various gluconeogenic and glycogenolytic enzymes, necessary for hepatic glucose production during glucose deprivation. The protein levels of phosphoenolpyruvate carboxykinase (PEPCK-C), the rate limiting enzyme of gluconeogenesis, were significantly decreased upon exposure to PCB126. The transcript levels of peroxisome proliferator-activated receptor alpha (Pparα) and several of its targets involved in fatty acid oxidation were also found to be time and dose-dependently decreased upon exposure to PCB126. As a novel finding, we show that PCB126 significantly decreases the phosphorylation of the nuclear transcription factor cAMP response element-binding protein (CREB), necessary for transcription of enzymes involved in hepatic glucose production. The decreased transcriptional activation of CREB, thus explain the integrative effects of PCB126 on both gluconeogenesis and fatty acid oxidation in causing the hepatotoxicity and impaired energy homeostasis