Long-term acetaminophen treatment induced liver fibrosis in mice and the involvement of Egr-1. (1st May 2017)

• Record Type: Journal Article
• Authors: Bai, Qingyun; Yan, Hongyu; Sheng, Yuchen; Jin, Yao; Shi, Liang; Ji, Lili; Wang, Zhengtao
• Is Part Of: Toxicology. Volume 382(2017)
• Page Start: 47
• Page End: 58
• Publication Date: 2017-05-01
• Subjects: APAP acetaminophen -- Egr-1 early growth response 1 -- COL collagen -- TGF-β transforming growth factor-β -- α-SMA α-smooth muscle actin -- NAPQI N-acetyl-p-benzoquinoneimine -- ECMs extracellular matrix proteins -- OTC over-the-counter -- ALF acute liver failure -- ALT/AST alanine/aspartate aminotransferase -- ELISA enzyme-linked immunosorbent assay -- ERK extracellular regulated protein kinases -- TALEN transcription activator-like effector nucleases -- H&E haematoxylin-eosin -- FBS fetal bovine serum -- SEM standard error of the mean -- TIMP tissue inhibitor of metalloproteinase -- BMP bone morphogenetic protein -- MMP matrix metalloproteinase -- HSC shepatic stellate cells; Acetaminophen -- Liver fibrosis -- Egr-1 -- HSCs activation; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2017.03.008
• Languages: English
• ISSNs: 0300-483X

Abstract

Graphical abstract: Highlights: Long-term APAP treatment led to collagen deposition. Long-term APAP treatment led to HSCs activation. Long-term APAP treatment led to the phosphorylation of Smad2/3 and ERK1/2. APAP toxic metabolite led to the activation of hepatic stellate LX2 cells. Egr-1 deletion mice were more sensitive to APAP-induced liver fibrosis. Abstract: Acetaminophen (APAP)-induced acute liver injury has already been well studied. However, whether long-term administration of APAP will cause liver fibrosis is still not very clear. This study aims to investigate the liver fibrosis in mice induced by long-term APAP treatment and the involvement of early growth response 1 (Egr-1). C57BL/6 mice were orally given with APAP (200, 300 mg/kg) for 2, 6 or 10 weeks, respectively. Liver hydroxyproline content, collagen deposition and inflammatory cells infiltration were increased in mice treated with APAP (200, 300 mg/kg) for 6 or 10 weeks. Liver mRNA expression of collagen (COL)1a1, Col3a1, transforming growth factor-β (TGF-β) and serum contents of COL1, COL3, TGF-β were all increased in APAP-treated mice. Liver expression of α-smooth muscle actin (α-SMA) and phosphorylated ERK1/2 and Smad2/3 were all increased in APAP-treated mice. Furthermore, increased liver mRNA expression of Egr-1 and its subsequent nuclear translocation were found in APAP-treated mice. Egr-1 knock-out mice were further applied. APAP-induced liver fibrosis was found to be more serious in Egr-1 knock-out mice. N-acetyl-p-benzoquinoneimine (NAPQI), the APAP hepatotoxic metabolite, increased cellular mRNA expression of α-SMA, Col1a1, Col3a1, TGF-β, induced ERK1/2 and Smad2/3 phosphorylation and Egr-1 nuclear translocation in hepatic stellate LX2 cells. In conclusion, long-term administration of APAP induced liver fibrosis in mice, and Egr-1 was critically involved in this process. This study points out a warning and reference for patients with long-term APAP ingestion in clinic.