Hepatic signalling disruption by pollutant Polychlorinated biphenyls in steatohepatitis |
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| Affiliation: | 1. Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA;2. Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA;3. Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202, USA;4. The Robley Rex Veterans Affairs Medical Center, Louisville, KY 40206, USA;5. The Jewish Hospital Liver Transplant Program, Louisville, KY 40202, USA;6. The Proteomics Core, University of Louisville School of Medicine, Louisville, KY 40202, USA;7. Hepatobiology & Toxicology Center, University of Louisville School of Medicine, Louisville, KY 40202, USA;8. University of Louisville Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA;9. University of Louisville Superfund Research Program, University of Louisville, Louisville, KY 40202, USA;1. Division of Human Reproduction and Developmental Genetics, The Women''s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China;2. Institute of Genetics, Department of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China;1. School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia;2. School of Pharmacy, The University of Queensland, Wooloongabba, QLD 4102, Australia;3. Department of Pharmacy, Xinhua College of Sun Yat-sen University, Guangzhou 510520, China;4. Department of Immunology, Monash University, Melbourne, VIC 3004, Australia;1. Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, No.12 Mid. Wulumuqi Road, Shanghai 200040, PR China;2. Department of Neurology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, No.110 Ganhe Road, Shanghai 200437, PR China;3. Department of Cardiology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, No.110 Ganhe Road, Shanghai 200437, PR China |
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| Abstract: | BackgroundPolychlorinated biphenyl-mediated steatohepatitis has been shown to be due in part to inhibition of epidermal growth factor receptor (EGFR) signalling. EGFR signalling regulates many facets of hepatocyte function, but it is unclear which other kinases and pathways are involved in the development of toxicant-associated steatohepatitis (TASH).MethodsComparative hepatic phosphoproteomic analysis was used to identify which kinases were affected by either PCB exposure (Aroclor 1260 mixture), high fat diet (HFD), or their interaction in a chronic exposure model of TASH. Cellular assays and western blot analysis were used to validate the phosphoproteomic findings.Results1760 unique phosphorylated peptides were identified and of those 588 were significantly different. PCB exposure and dietary interaction promoted a near 25% reduction of hepatic phospho-peptides. Leptin and insulin signalling were pathways highly affected by PCB exposure and liver necrosis was a pathologic ontology over represented due to interaction between PCBs and a HFD. Casein kinase 2 (CK2), Extracellular regulated kinase (ERK), Protein kinase B (AKT), and Cyclin dependent kinase (CDK) activity were demonstrated to be downregulated after PCB exposure and this downregulation was exacerbated with a HFD. PCB exposure led to a loss of hepatic CK2 subunit expression limiting CK2 kinase activity and negatively regulating caspase-3 (CASP3). PCBs promoted secondary necrosis in vitro validating the latter observation. The loss of hepatic phosphoprotein signalling appeared to be due to decreased signal transduction rather than phosphatase upregulation.ConclusionsPCBs are signal disrupting chemicals that promote secondary necrosis through affecting a myriad of liver processes including metabolism and cellular maintenance. PCB exposure, particularly with interaction with a HFD greatly down-regulates the hepatic kinome. More data are needed on signalling disruption and its impact on liver health. |
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