Josiah E Hardesty1, Banrida Wahlang2, K Cameron Falkner3, Hongxue Shi4, Jian Jin5, Daniel Wilkey6, Michael Merchant7, Corey Watson8, Russell A Prough9, Matthew C Cave10. 1. Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA. Electronic address: Josiah.hardesty@louisville.edu. 2. Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202, USA; University of Louisville Superfund Research Program, University of Louisville, Louisville, KY 40202, USA. Electronic address: banrida.wahlang@louisville.edu. 3. Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202, USA; Hepatobiology & Toxicology Center, University of Louisville School of Medicine, Louisville, KY 40202, USA. Electronic address: cam.falkner@louisville.edu. 4. Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA. Electronic address: hongxue.shi@northwestern.edu. 5. Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA. Electronic address: jian.jin@louisville.edu. 6. The Proteomics Core, University of Louisville School of Medicine, Louisville, KY 40202, USA. Electronic address: daniel.wilkey@louisville.edu. 7. The Proteomics Core, University of Louisville School of Medicine, Louisville, KY 40202, USA. Electronic address: michael.merchant@louisville.edu. 8. Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA. Electronic address: corey.watson@louisville.edu. 9. Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA. Electronic address: russell.prough@louisville.edu. 10. Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202, USA; The Robley Rex Veterans Affairs Medical Center, Louisville, KY 40206, USA; The Jewish Hospital Liver Transplant Program, Louisville, KY 40202, USA; Hepatobiology & Toxicology Center, University of Louisville School of Medicine, Louisville, KY 40202, USA; University of Louisville Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA; University of Louisville Superfund Research Program, University of Louisville, Louisville, KY 40202, USA. Electronic address: matt.cave@louisville.edu.
Abstract
BACKGROUND: Polychlorinated 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). METHODS: Comparative 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. RESULTS: 1760 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. CONCLUSIONS: PCBs 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. Published by Elsevier Inc.
BACKGROUND:Polychlorinated 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). METHODS: Comparative 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. RESULTS: 1760 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. CONCLUSIONS:PCBs are signal disrupting chemicals that promote secondary necrosisthrough 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. Published by Elsevier Inc.
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