Hepatic signalling disruption by pollutant Polychlorinated biphenyls in steatohepatitis

• Published in: Cellular signalling Vol. 53; pp. 132 - 139
• Main Authors: Hardesty, Josiah E., Wahlang, Banrida, Falkner, K. Cameron, Shi, Hongxue, Jin, Jian, Wilkey, Daniel, Merchant, Michael, Watson, Corey, Prough, Russell A., Cave, Matthew C.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01-01-2019
• Subjects: Animals; Casein kinase 2; Cell Line; Environmental Pollutants - adverse effects; Fatty Liver - chemically induced; Fatty Liver - metabolism; Hepatocytes - drug effects; Hepatocytes - metabolism; Humans; Male; Mice, Inbred C57BL; Phosphorylation - drug effects; Polychlorinated biphenyls; Polychlorinated Biphenyls - adverse effects; Secondary necrosis; Signal Transduction - drug effects; Signalling disruption; FXR; PCBs; Signalling disruption; NAFLD; MDCs; Secondary necrosis; HFD; LXR; SDCs; CDK; CK2; EGFR; EDCs; NRF2; PI3K; FDR; CASP3; PP2α; Casein kinase 2; CD; TASH; HNF4α; AKT; PTP1B; CAR; Polychlorinated biphenyls; FASP; NHANES; GAPDH; CK-18; ERK
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2018.10.004

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).
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.
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.
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.
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•PCBs are signalling disrupting chemicals that downregulate 25% of the hepatic phospho-proteome in steatohepatitis.•PCBs prevent Casein Kinase 2 negative regulation of Caspase 3.•PCBs promote secondary necrosis.