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Epidermal Growth Factor Receptor (EGFR) Signaling: A Double‐edged Sword in Acetaminophen‐induced Liver Injury and Regeneration
Author(s) -
Bhushan Bharat,
Borude Prachi,
Manley Michael W.,
Chavan Hemant,
Xie Yuchao,
Du Kuo,
McGill Mitch,
Lebofsky Margitta,
Jaeschke Hartmut,
Kasturi Partha,
Apte Udayan
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.56.9
Subject(s) - acetaminophen , glutathione , chemistry , pharmacology , epidermal growth factor receptor , mitochondrion , liver injury , egfr inhibitors , cancer research , receptor , biochemistry , medicine , enzyme
Epidermal Growth Factor Receptor (EGFR) signaling is known to play a crucial role in hepatocyte proliferation, but its role in liver injury has not been demonstrated. Its role in acetaminophen (APAP)‐mediated acute liver injury and subsequent liver regeneration is completely unknown, which was investigated in this study. Remarkable activation of EGFR was noted as early as 30 min after APAP treatment in mice and it remained activated up to 24 hr. Activation of EGFR was strikingly increased at higher, non‐regenerating, dose of APAP. Treatment of mice with an EGFR inhibitor (EGFRI), Canertinib, 1 hr post‐APAP caused robust inhibition of EGFR activation, resulting in striking reduction in APAP‐induced liver injury. APAP‐protein adducts formation and glutathione depletion were not altered indicating APAP metabolic activation was not affected by EGFRI. Further, APAP‐mediated JNK activation (a key mediator of APAP toxicity) and its mitochondrial translocation were not altered by EGFRI. However, EGFRI treatment reduced APAP‐mediated mitochondrial translocation of activated EGFR, nitrotyrosine protein adduct formation in mitochondria and blocked release of endonucleases from mitochondria, which are responsible for DNA damage and necrosis. Further, bioenergetics analysis with Seahorse Technology showed that EGFRI treatment rescued APAP‐mediated decreased mitochondrial function as indicated by restored mitochondrial coupling and maximal respiration. Whereas, treatment with NAC 4 hr after APAP in mice did not show any protection, treatment with EGFRI, 4 hr post‐APAP, showed remarkable decrease in liver injury. Treatment with Phorone (a glutathione depletory agent), standalone, also caused robust EGFR activation, whereas, replenishment of glutathione by N‐acetyl cysteine (NAC) treatment, 1.5 hr after APAP in mice inhibited APAP‐mediated EGFR activation, suggesting role of glutathione depletion after APAP overdose in activation of EGFR. EGFR activation was also observed in primary human hepatocytes after APAP treatment, preceding elevation of toxicity markers. Interestingly, delayed treatment with EGFRI, 12 hr post‐APAP, did not alter peak injury but caused remarkable impairment of liver regeneration response resulting in sustained injury and decreased survival after APAP overdose in mice. Impairment of liver regeneration was due to inhibition cyclin D1 induction and phosphorylation of retinoblastoma protein. In conclusion, our study has revealed an extremely novel role of EGFR both in development of APAP injury and in stimulation of subsequent compensatory liver regeneration after APAP overdose. Support or Funding Information This project was supported by grants from the NCRR 5P20RR021940‐07, NIDDK R01DK098414, NIEHS T32 ES007079 and Liver Scholar Award (Udayan Apte) by AASLD/American Liver Foundation