Reduction in activating transcription factor 4 promotes carbon tetrachloride and lipopolysaccharide/D‑galactosamine‑mediated liver injury in mice

Zhao,Xiaofang; Zhou,Hong; Cheng,Ying; Yu,Wenjing; Luo,Guosong; Duan,Chunyan; Yao,Fuli; Xiao,Bin; Feng,Chunhong; Xia,Xianming; Wei,Mei; Wang,Yong; Li,Jing; Dai,Rongyang

doi:10.3892/mmr.2018.9080

Reduction in activating transcription factor 4 promotes carbon tetrachloride and lipopolysaccharide/D‑galactosamine‑mediated liver injury in mice

Authors:
- Xiaofang Zhao
- Hong Zhou
- Ying Cheng
- Wenjing Yu
- Guosong Luo
- Chunyan Duan
- Fuli Yao
- Bin Xiao
- Chunhong Feng
- Xianming Xia
- Mei Wei
- Yong Wang
- Jing Li
- Rongyang Dai
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Affiliations: Department of Biochemistry and Molecular Biology, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China, Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China, Department of Liver Diseases, The Affiliated Hospital of Chinese Traditional Medicine, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China, Liver Diseases Laboratory, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
Published online on: May 29, 2018 https://doi.org/10.3892/mmr.2018.9080
Pages: 1718-1725

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Abstract

Although activating transcription factor 4 (ATF4) is involved in the regulation of numerous biological functions, whether ATF4 has a direct role in liver injury is unknown. The aim of the present study was to investigate the role of ATF4 in liver injury using mouse models. The results revealed that ATF4 protein is expressed markedly higher in the mouse liver when in comparison with other tissues. Notably, tunicamycin treatment, an endoplasmic reticulum (ER) stress inducer, induced the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), but decreased ATF4 protein levels in the mouse liver. This suggested an unconventional regulation pattern of ATF4 protein not associated with ER stress or eIF2α. In addition, it was also observed that the liver levels of ATF4 protein were significantly reduced upon chronic liver injury induced by carbon tetrachloride (CCl4). ATF4 protein was also decreased in acute liver injury induced by lipopolysaccharide (LPS) plus D‑galactosamine (D‑GalN). Furthermore, the results revealed that knockdown of ATF4 by injecting ATF4‑targeting Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)‑CRISPR associated protein 9 plasmids exacerbated CCl4 and LPS/D‑GalN‑induced liver injury as demonstrated by elevated serum aspartate transaminase and alanine aminotransferase levels. ATF4 suppression also enhanced CCl4 and LPS/D‑GalN mediated c‑Jun N‑terminal kinase activation. By contrast, ATF4 overexpression alleviated CCl4 and LPS/D‑GalN‑induced liver injury. Taken together, these observations suggested that ATF4 may serve a protective role in the mouse liver.

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