Data from: PCB126 inhibits the activation of AMPK-CREB signal transduction required for energy sensing in liver

3,3’,4,4’,5-pentachlorobiphenyl (PCB126), a dioxin-like PCB, elicits toxicity through a wide array of non-carcinogenic effects, including metabolic syndrome, wasting, and non-alcoholic fatty-liver disease (NAFLD). 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 d, prior euthanasia. A subset of rats from each group were fasted for 12h (vehicle (n=6) and PCB126 (n=4)). Rats only showed significant weight loss between days 14 and 28 (P<0.05) and some mortality (P=0.0413). 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.

3,3’,4,4’,5-五氯联苯（PCB126）是一种类二噁英多氯联苯（dioxin-like PCB），可通过多种非致癌效应引发毒性，涵盖代谢综合征、消瘦症及非酒精性脂肪肝病（NAFLD）。既往本研究团队曾报道，在脂质蓄积早期发作前，糖异生（gluconeogenesis）相关的多种酶的转录水平出现下调。因此本研究旨在明确长期暴露后，糖异生酶表达下调对肝脏生长、体重及代谢的影响。

选取体重75~100 g的雄性斯普拉格-道利大鼠（Sprague-Dawley rats），喂食定制AIN-93G合成饲料，于安乐死处死前28天，以单剂量腹腔注射（ip）大豆油（5 ml/kg体重；n=14）或PCB126（5 µmol/kg；n=15）。两组各取亚群大鼠禁食12小时：溶剂对照组（n=6）与PCB126处理组（n=4）。

大鼠仅在第14天至第28天期间出现显著体重下降（P<0.05），且伴随一定死亡率（P=0.0413）。与既往研究结果一致，糖异生相关酶（Pepck-c、G6Pase、Sds、Pc及Ldh-A）及糖原分解（glycogenolysis）相关酶Pygl的表达水平均显著下调。在禁食12小时的PCB126处理大鼠中，上述酶的表达下调可降低肝脏通过糖原及糖异生底物合成葡萄糖的能力，进而加重低血糖症状。

此外，PCB126可诱发肝脏脂肪变性（hepatic steatosis），并下调脂肪酸氧化（fatty-acid oxidation）所需的转录因子过氧化物酶体增殖物激活受体α（Pparα）及其靶基因的表达。本研究观察到的禁食代谢多通路紊乱，源于腺苷酸活化蛋白激酶（AMP-activated protein kinase, AMPK）与环腺苷酸应答元件结合蛋白（CREB）信号通路的激活受抑；这两条通路是感知能量匮乏、诱导肝脏响应PCB126诱发的燃料危机相关酶表达的关键通路。