Proteomic Analysis Reveals Novel Mechanisms by Which Polychlorinated Biphenyls Compromise the Liver Promoting Diet-Induced Steatohepatitis

Josiah E. Hardesty, Banrida Wahlang, K. Cameron Falkner, Hongxue Shi, Jian Jin, Yun Zhou, Daniel W. Wilkey, Michael L. Merchant, Corey T. Watson, Wenke Feng, Andrew J. Morris, Bernhard Hennig, Russell A. Prough, Matthew C. Cave

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Environmental pollution contributes to fatty liver disease pathogenesis. Polychlorinated biphenyl (PCB) exposures have been associated with liver enzyme elevation and suspected steatohepatitis in cohort studies. Male mice treated with the commercial PCB mixture, Aroclor 1260 (20 mg/kg), and fed high fat diet (HFD) for 12 weeks developed steatohepatitis. Receptor-based modes of action including inhibition of the epidermal growth factor (EGF) receptor were previously proposed, but other mechanisms likely exist. Objectives were to identify and validate the pathways, transcription factors, and mechanisms responsible for the steatohepatitis associated with PCB and HFD coexposures. Comparative proteomics analysis was performed in archived mouse liver samples from the aforementioned chronic exposure study. Pathway and transcription factor analysis (TFA) was performed, and selected results were validated. Liver proteomics detected 1103 unique proteins. Aroclor 1260 upregulated 154 and downregulated 93 of these. Aroclor 1260 + HFD coexposures affected 55 pathways including glutathione metabolism, intermediary metabolism, and cytoskeletal remodeling. TFA of Aroclor 1260 treatment demonstrated alterations in the function of 42 transcription factors including downregulation of NRF2 and key nuclear receptors previously demonstrated to protect against steatohepatitis (e.g., HNF4α, FXR, PPARα/I/I, etc.). Validation studies demonstrated that Aroclor 1260 significantly reduced HNF4α protein levels, while Aroclor 1260 + HFD reduced expression of the HNF4α target gene, albumin, in vivo. Aroclor 1260 attenuated EGF-dependent HNF4α phosphorylation and target gene activation in vitro. Aroclor 1260 reduced levels of NRF2, its target genes, and glutathione in vivo. Aroclor 1260 attenuated EGF-dependent NRF2 upregulation, in vitro. Aroclor 1260 indirectly activated hepatic stellate cells in vitro via induction of hepatocyte-derived TGFβ. PCB exposures adversely impacted transcription factors regulating liver protection, function, and fibrosis. PCBs, thus, compromised the liver by reducing its protective responses against nutritional stress to promote diet-induced steatohepatitis. The identified mechanisms by which environmental pollutants influence fatty liver disease pathogenesis require confirmation in humans.

Original languageEnglish
Pages (from-to)1582-1594
Number of pages13
JournalJournal of Proteome Research
Volume18
Issue number4
DOIs
StatePublished - Apr 5 2019

Bibliographical note

Funding Information:
This work was supported in part by the National Institute of Environmental Health Sciences [F31ES028982, R35ES028373, R01ES021375, P42ES023716, and P42ES007380], the National Institute of General Medical Sciences [P20GM113226], and the National Institute on Alcohol Abuse and Alcoholism [P50AA024337]. The authors thank Dr. Heather Clair for her consultation on this study.

Publisher Copyright:
© Copyright 2019 American Chemical Society.

Keywords

  • Aroclor 1260
  • EGFR
  • HNF4α
  • TASH
  • liver
  • metabolism
  • polychlorinated biphenyl
  • steatohepatitis

ASJC Scopus subject areas

  • Biochemistry
  • Chemistry (all)

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