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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

Authors: Yan-zi Yang1, Xiao-juan Zhao1, Hong-jiang Xu2, Shan-chun Wang2, Ying Pan1, Shui-juan Wang1, Qiang Xu1, Rui-qing Jiao1, Hong-mei Gu2, Ling-dong Kong1
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
Correspondence to: Hong-mei Gu: ghm@cttq.com, Ling-dong Kong: kongld@nju.edu.cn,
DOI: 10.1038/s41401-018-0194-4
Received: 30 May 2018
Accepted: 8 November 2018
Advance online: 19 December 2018

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

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