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An Advanced Murine Model for Nonalcoholic Steatohepatitis in Association with Type 2 Diabetes
Published on: April 26, 2019
Hepatic signalling disruption by pollutant Polychlorinated biphenyls in steatohepatitis
Josiah E Hardesty1, Banrida Wahlang2, K Cameron Falkner3
1Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, USA.
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.
Insights
Polychlorinated biphenyls (PCBs) disrupt liver cell signaling, causing steatohepatitis. Combined with a high-fat diet, PCBs significantly down-regulate liver kinases, leading to cell death.
Area of Science:
- Hepatology
- Toxicology
- Biochemistry
Background:
- Polychlorinated biphenyls (PCBs) are known to cause steatohepatitis partly by inhibiting epidermal growth factor receptor (EGFR) signaling.
- The specific kinases and pathways involved in toxicant-associated steatohepatitis (TASH) development remain unclear.
Purpose of the Study:
- To identify kinases and pathways affected by PCB exposure, high-fat diet (HFD), or their interaction in TASH.
- To validate phosphoproteomic findings using cellular assays and western blot analysis.
Main Methods:
- Comparative hepatic phosphoproteomic analysis was performed on a chronic TASH model.
- Exposure involved Aroclor 1260 (PCB mixture) and/or HFD.
- Cellular assays and western blot analysis were used for validation.
Main Results:
- PCB exposure and HFD interaction reduced hepatic phosphopeptides by ~25%.
- Leptin and insulin signaling pathways were significantly affected by PCB exposure.
- Casein kinase 2 (CK2), ERK, AKT, and CDK activities were downregulated by PCBs, exacerbated by HFD.
- PCB exposure led to loss of hepatic CK2 subunit expression, downregulating caspase-3 (CASP3) and promoting secondary necrosis.
Conclusions:
- PCBs are signal-disrupting chemicals that promote secondary necrosis by affecting liver metabolism and maintenance.
- PCB exposure, especially with HFD, significantly down-regulates the hepatic kinome.
- Further research is needed on signaling disruption's impact on liver health.
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