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  2. Magnesium isoglycyrrhizinate ameliorates high fructose-induced liver fibrosis in rat by increasing miR-375-3p to suppress JAK2/STAT3 pathway and TGF-β1/Smad signaling

Magnesium isoglycyrrhizinate ameliorates high fructose-induced liver fibrosis in rat by increasing miR-375-3p to suppress JAK2/STAT3 pathway and TGF-β1/Smad signaling

  • Acta Pharmacol Sin. 2019 Jul;40(7):879-894. doi: 10.1038/s41401-018-0194-4.
Yan-Zi Yang  # 1 Xiao-Juan Zhao  # 1 Hong-Jiang Xu 2 Shan-Chun Wang 2 Ying Pan 1 Shui-Juan Wang 1 Qiang Xu 1 Rui-Qing Jiao 1 Hong-Mei Gu 3 Ling-Dong Kong 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China.
  • 2 Jiangsu Key Laboratory of Targeted Antiviral Research, Chia Tai Tianqing Pharmaceutical Group Co., Ltd, Nanjing, 210023, China.
  • 3 Jiangsu Key Laboratory of Targeted Antiviral Research, Chia Tai Tianqing Pharmaceutical Group Co., Ltd, Nanjing, 210023, China. [email protected].
  • 4 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China. [email protected].
  • # Contributed equally.
Abstract

Increasing evidence has demonstrated that excessive fructose intake induces liver fibrosis. Epithelial-mesenchymal transition (EMT) driven by transforming growth factor-β1 (TGF-β1)/mothers against decapentaplegic homolog (Smad) signaling activation promotes the occurrence and development of liver fibrosis. Magnesium isoglycyrrhizinate is clinically used as a hepatoprotective agent to treat liver fibrosis, but its underlying molecular mechanism has not been identified. Using a rat model, we found that high fructose intake reduced MicroRNA (miR)-375-3p expression and activated the janus-activating kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) cascade and TGF-β1/Smad signaling, which is consistent with the EMT and liver fibrosis. To further verify these observations, BRL-3A cells and/or primary rat hepatocytes were exposed to high fructose and/or transfected with a miR-375-3p mimic or inhibitor or treated with a JAK2 Inhibitor, and we found that the low expression of miR-375-3p could induce the JAK2/STAT3 pathway to activate TGF-β1/Smad signaling and promote the EMT. Magnesium isoglycyrrhizinate was found to ameliorate high fructose-induced EMT and liver fibrosis in rats. More importantly, magnesium isoglycyrrhizinate increased miR-375-3p expression to suppress the JAK2/STAT3 pathway and TGF-β1/Smad signaling in these animal and cell models. This study provides evidence showing that magnesium isoglycyrrhizinate attenuates liver fibrosis associated with a high fructose diet.

Keywords

EMT; JAK2/STAT3 pathway; MicroRNA-375-3p; TGF-β1/Smad signaling; excessive fructose intake; magnesium isoglycyrrhizinate.

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