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Front. Pharmacol. | doi: 10.3389/fphar.2017.00976

Carnosic acid alleviates BDL-induced liver fibrosis through miR-29b-3p-mediated inhibition of the High-mobility group box 1/ Toll-like receptor 4 signaling pathway in rats

Shuai Zhang1, Zhecheng Wang1, Jie Zhu1, Ting Xu1, Yan Zhao1, Huanyu Zhao1, Fan Tang1, Zhenlu Li2, Junjun Zhou1, Dongyan Gao1, Xiaofeng Tian2 and  Jihong Yao1*
  • 1Department of Pharmacology, Dalian Medical University, China
  • 2Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, China

Fibrosis reflects a progression to liver cancer or cirrhosis of the liver. Recent studies have shown that high-mobility group box-1 (HMGB1) plays a major role in hepatic injury and fibrosis. Carnosic acid (CA), a compound extracted from rosemary, has been reported to alleviate alcoholic and nonalcoholic fatty liver injury. CA can also alleviate renal fibrosis. We hypothesized that CA might exert anti-liver fibrosis properties through an HMGB1-related pathway, and the results of the present study showed that CA treatment significantly protected against hepatic fibrosis in a bile duct ligation (BDL) rat model. CA reduced the liver expression of α-smooth muscle actin (α-SMA) and collagen 1 (Col-1). Importantly, we found that CA ameliorated the increase in HMGB1 and Toll-like receptor 4 (TLR4) caused by BDL, and inhibited NF-κB p65 nuclear translocation in fibrotic livers. In vitro, CA inhibited LX2 cell activation by inhibiting HMGB1/TLR4 signaling pathway. Furthermore, miR-29b-3p decreased HMGB1 expression, and a dual-luciferase assay validated these results. Moreover, CA down-regulated HMGB1 and inhibited LX2 cell activation, and these effects were significantly counteracted by antago-miR-29b-3p, indicating that the CA-mediated inhibition of HMGB1 expression might be miR-29b-3p dependent. Collectively, the results demonstrate that a miR-29b-3p/HMGB1/TLR4/NF-κB signaling pathway, which can be modulated by CA, is important in liver fibrosis, and indicate that CA might be a prospective therapeutic drug for liver fibrosis.

Abbreviations
Carnosic acid (CA); High-mobility group box 1 (HMGB1); Toll-like receptor 4 (TLR4); Nuclear factor kappa B (NF-κB); Bile duct ligation (BDL); Alanine aminotransferase (ALT); Aspartate aminotransferase (AST); α-Smooth muscle actin (α-SMA); Collagen 1 (Col-1); Matrix metalloprotein 9 (MMP9); Transforming Growth factor-beta 1 (TGF-β1); Transforming growth factor-beta receptor type 1 (TGF-β R1)
Key words: Carnosic acid; Bile duct ligation; High-mobility group box-1; miR-29b-3p; Liver fibrosis

Keywords: carnosic acid, bile duct ligation, High-mobility group box-1, miR-29b-3p, liver fibrosis

Received: 06 Jul 2017; Accepted: 21 Dec 2017.

Edited by:

David Sacerdoti, Università degli Studi di Padova, Italy

Reviewed by:

Mirko Pesce, Università degli Studi "G. d'Annunzio" Chieti - Pescara, Italy
Jiiang-Huei Jeng, National Taiwan University, Taiwan
Dr. SHAILENDRA P. SINGH, New York Medical College, United States  

Copyright: © 2017 Zhang, Wang, Zhu, Xu, Zhao, Zhao, Tang, Li, Zhou, Gao, Tian and Yao. 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) or licensor 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. Jihong Yao, Dalian Medical University, Department of Pharmacology, Dalian, 116044, Liaoning, China, yaojihong65@hotmail.com