title: PCB126-Induced Disruption in Gluconeogenesis and Fatty Acid Oxidation Precedes Fatty Liver in Male Rats.
abstract: 3,3',4,4',5-Pentachlorobiphenyl (PCB126), a dioxin-like polychlorinated biphenyl (PCB) and a potent aryl hydrocarbon receptor (AhR) agonist, is implicated in the disruption of both carbohydrate and lipid metabolism which ultimately leads to wasting disorders, metabolic disease, and nonalcoholic fatty liver disease. However, the mechanisms are unclear. Because liver is the target organ for PCB toxicity and responsible for metabolic homeostasis, we hypothesized that early disruption of glucose and lipid homeostasis contributes to later manifestations such as hepatic steatosis. To test this hypothesis, groups of male Sprague Dawley rats, fed on AIN-93G diet, were injected (intraperitoneal.) with a single bolus of PCB126 (5 µmol/kg) at various time intervals between 9 h and 12 days prior to euthanasia. An early decrease in serum glucose and a gradual decrease in serum triglycerides were observed over time. Liver lipid accumulation was most severe at 6 and 12 days of exposure. Transcript levels of cytosolic phosphoenol-pyruvate carboxykinase (Pepck-c/Pck1) and glucose transporter (Glut2/Slc2a2) involved in gluconeogenesis and hepatic glucose transport were time-dependently downregulated between 9 h and 12 days of PCB126 exposure. Additionally, transcript levels of Pparα, and its targets acyl-CoA oxidase (Acox1) and hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2), were also downregulated, indicating changes in peroxisomal fatty acid oxidation and ketogenesis. In a separate animal study, we found that the measured changes in the transcript levels of Pepck-c, Glut2, Pparα, Acox1, and Hmgcs2 were also dose dependent. Furthermore, PCB126-induced effects on Pepck-c were demonstrated to be AhR dependent in rat H4IIE hepatocytes. These results indicate that PCB126-induced wasting and steatosis are preceded initially by (1) decreased serum glucose caused by decreased hepatic glucose production, followed by (2) decreased peroxisomal fatty acid oxidation.
authors.affiliation: *Interdisciplinary Graduate Program in Human Toxicology; Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, Iowa;
authors.forename: Gopi S
authors.initials: GS
authors.lastname: Gadupudi
authors.affiliation: *Interdisciplinary Graduate Program in Human Toxicology; Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, Iowa;
authors.forename: William D
authors.initials: WD
authors.lastname: Klaren
authors.affiliation: Department of Pathobiology and Population Medicine, Mississippi State University, Starkville, Mississippi; and.
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Olivier
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, Iowa.
authors.forename: Aloysius J
authors.initials: AJ
authors.lastname: Klingelhutz
authors.affiliation: *Interdisciplinary Graduate Program in Human Toxicology; Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, Iowa; larry-robertson@uiowa.edu.
authors.forename: Larry W
authors.initials: LW
authors.lastname: Robertson
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000139:chemically induced* / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D005227:Fatty Acids; D047908:Intracellular Signaling Peptides and Proteins; D018336:Receptors, Aryl Hydrocarbon; D014280:Triglycerides; D011078:Polychlorinated Biphenyls; C582554:Pck1 protein, rat; D010729:Phosphoenolpyruvate Carboxykinase (GTP); C023035:3,4,5,3',4'-pentachlorobiphenyl
keywords: PCB126; PPAR; fatty acid oxidation; gluconeogenesis; peroxisomes; steatosis