Journal article
PCB126 Inhibits the Activation of AMPK-CREB Signal Transduction Required for Energy Sensing in Liver
Toxicological sciences, Vol.163(2), pp.440-453
06/2018
DOI: 10.1093/toxsci/kfy041
PMCID: PMC5974782
PMID: 29474705
Abstract
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.
Details
- Title: Subtitle
- PCB126 Inhibits the Activation of AMPK-CREB Signal Transduction Required for Energy Sensing in Liver
- Creators
- Gopi S Gadupudi - Department of Pathology, Carver College of Medicine, The University of Iowa, Iowa City, IowaBenjamin A Elser - Department of Pathology, Carver College of Medicine, The University of Iowa, Iowa City, IowaFabian A Sandgruber - Department of Pathology, Carver College of Medicine, The University of Iowa, Iowa City, IowaXueshu Li - Department of Pathology, Carver College of Medicine, The University of Iowa, Iowa City, IowaKatherine N Gibson-Corley - Department of Pathology, Carver College of Medicine, The University of Iowa, Iowa City, IowaLarry W Robertson - Department of Pathology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa
- Resource Type
- Journal article
- Publication Details
- Toxicological sciences, Vol.163(2), pp.440-453
- Publisher
- Oxford University Press
- DOI
- 10.1093/toxsci/kfy041
- PMID
- 29474705
- PMCID
- PMC5974782
- ISSN
- 1096-6080
- eISSN
- 1096-0929
- Grant note
- P42 ES013661 / ; ; ;
- Language
- English
- Date published
- 06/2018
- Academic Unit
- Occupational and Environmental Health; Pathology; Iowa Superfund Research Program; Ophthalmology and Visual Sciences
- Record Identifier
- 9984002339402771
Metrics
23 Record Views