Jiahuan Li1, Xiaoling Deng1, Tao Bai1, Shuhan Wang1, Qianqian Jiang1, Keshu Xu2. 1. Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. 2. Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: xl2017@hust.edu.cn.
Abstract
AIMS: Resolvin D1 (RvD1), a potent endogenous lipid mediator converted from docosahexaenoic acid (DHA), has exert anti-inflammatory and antioxidant effects in many preclinical disease models, but its potential role in non-alcoholic steatohepatitis (NASH) remains elusive. This study was performed to investigate the protective effects and mechanisms of RvD1 in NASH. MAIN METHODS: In vivo, male C57BL/6 mice were fed an MCD diet for 4 weeks to induce NASH. RvD1 was added in the last 2 weeks of the feeding period. In vitro, lipopolysaccharide (LPS)-activated RAW264.7 macrophages were pretreated with increasing concentrations of RvD1. Serum liver functional markers and hepatic oxidative stress indicators were measured biochemically. Mouse liver tissue sections were stained with hematoxylin-eosin, oil red O, and Masson's trichrome to assess the severity of steatohepatitis, steatosis and fibrosis. The qRT-PCR, immunohistochemistry and Western blotting assays were applied to analyse mechanisms underlying RvD1 protection in NASH. KEY FINDINGS: In vivo, RvD1 significantly attenuates steatohepatitis in MCD diet-fed mice by modulating key events, including steatosis, inflammation, oxidative stress and fibrosis in the progression of NASH. In vitro, RvD1 also represses LPS-induced inflammation in RAW264.7 cells. These effects may be mainly attributed to RvD1 markedly suppressing excessive inflammatory responses via the inhibition of the TLR4-MyD88-mediated NF-κB and MAPK signalling pathways as well as enhancing antioxidation capacity via the activation of the Nrf2 pathway. SIGNIFICANCE: These results demonstrate that RvD1 is a promising hepatoprotective agent for the therapy of NASH.
AIMS: Resolvin D1 (RvD1), a potent endogenous lipid mediator converted from docosahexaenoic acid (DHA), has exert anti-inflammatory and antioxidant effects in many preclinical disease models, but its potential role in non-alcoholic steatohepatitis (NASH) remains elusive. This study was performed to investigate the protective effects and mechanisms of RvD1 in NASH. MAIN METHODS: In vivo, male C57BL/6 mice were fed an MCD diet for 4 weeks to induce NASH. RvD1 was added in the last 2 weeks of the feeding period. In vitro, lipopolysaccharide (LPS)-activated RAW264.7 macrophages were pretreated with increasing concentrations of RvD1. Serum liver functional markers and hepatic oxidative stress indicators were measured biochemically. Mouse liver tissue sections were stained with hematoxylin-eosin, oil red O, and Masson's trichrome to assess the severity of steatohepatitis, steatosis and fibrosis. The qRT-PCR, immunohistochemistry and Western blotting assays were applied to analyse mechanisms underlying RvD1 protection in NASH. KEY FINDINGS: In vivo, RvD1 significantly attenuates steatohepatitis in MCD diet-fed mice by modulating key events, including steatosis, inflammation, oxidative stress and fibrosis in the progression of NASH. In vitro, RvD1 also represses LPS-induced inflammation in RAW264.7 cells. These effects may be mainly attributed to RvD1 markedly suppressing excessive inflammatory responses via the inhibition of the TLR4-MyD88-mediated NF-κB and MAPK signalling pathways as well as enhancing antioxidation capacity via the activation of the Nrf2 pathway. SIGNIFICANCE: These results demonstrate that RvD1 is a promising hepatoprotective agent for the therapy of NASH.