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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2018.01344

Inositol-Requiring Enzyme 1 Alpha Endoribonuclease Specific Inhibitor STF-083010 Alleviates Carbon Tetrachloride Induced Liver Injury and Liver Fibrosis in Mice

Qian-Qian Chen1, Cheng Zhang2, Ming-Qiang Qin1, Jian Li2, Hua Wang2,  De-Xiang Xu2* and  Jian-Qing Wang3*
  • 1Second Hospital of Anhui Medical University, China
  • 2Department of Health Toxicology, School of Public Health, Anhui Medical University, China
  • 3Anhui Medical University, China

Accumulating data demonstrated that hepatic endoplasmic reticulum (ER) stress was involved in the pathogenesis of liver fibrosis. Long-term chronic hepatocyte death contributed to liver fibrosis initiation and progression. Previous researches reported that ER stress sensor inositol-requiring enzyme 1 alpha (IRE1α) was first activated in the process of liver fibrosis. STF-083010 was an IRE1α RNase specific inhibitor. This study aimed to explore the effects of STF-083010 on carbon tetrachloride (CCl4)-induced liver injury and subsequent liver fibrosis. Mice were intraperitoneally (i.p.) injected with CCl4 (0.15 ml/kg) for 8 weeks. In STF-083010+CCl4 group, mice were injected with STF-083010 (30 mg/kg, i.p.), twice a week, beginning from the sixth week after CCl4 injection. CCl4 treatment markedly enhanced the levels of serum ALT, TBIL, DBIL and TBA, and STF-083010 had obviously extenuated CCl4-induced exaltation of ALT, DBIL and TBA levels. CCl4-induced hepatic hydroxyproline and collagen Ι, major indicators of liver fibrosis, were alleviated by STF-083010. Additionally, CCl4-induced α-smooth muscle actin, a marker for hepatic stellate cells activation, was obviously attenuated in STF-083010-treated mice. Moreover, CCl4-induced upregulation of inflammatory cytokines was suppressed by STF-083010. Mechanistic exploration found that hepatic miR-122 was downregulated in CCl4-treated mice. Hepatic MCP1, CTGF, P4HA1, Col1α1 and Mmp9, target genes of miR-122, were upregulated in CCl4-treated mice. Interestingly, STF-083010 reversed CCl4-induced hepatic miR-122 downregulation. Correspondingly, STF-083010 inhibited CCl4-induced upregulation of miR-122 target genes. This study provides partial evidence that STF-083010 alleviated CCl4-induced liver injury and thus protected against liver fibrosis associated with hepatic miR-122.

Keywords: inositol-requiring enzyme 1 alpha, STF-083010, miR-122, Hepatocyte death, liver fibrosis

Received: 30 Aug 2018; Accepted: 31 Oct 2018.

Edited by:

David Sacerdoti, Università degli Studi di Padova, Italy

Reviewed by:

Leo A. Van Grunsven, Vrije Universiteit Brussel, Belgium
Dr. SHAILENDRA P. SINGH, New York Medical College, United States  

Copyright: © 2018 Chen, Zhang, Qin, Li, Wang, Xu and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. De-Xiang Xu, Department of Health Toxicology, School of Public Health, Anhui Medical University, Hefei, China, xudex@126.com
Dr. Jian-Qing Wang, Anhui Medical University, Hefei, China, jianqingwang81@126.com