Exosomal miR-199a-5p promotes hepatic lipid accumulation by modulating MST1 expression and fatty acid metabolism
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ORIGINAL ARTICLE
Exosomal miR‑199a‑5p promotes hepatic lipid accumulation by modulating MST1 expression and fatty acid metabolism Yuhan Li1,2,5 · Yansong Luan1,2 · Jianning Li1,2 · Hui Song1,2 · Yan Li1,2 · Hi Qi1 · Bo Sun3 · Peng Zhang3 · Xianxian Wu5 · Xing Liu5 · Yanhui Yang1,2 · Wufan Tao4 · Lei Cai6 · Zhiwei Yang5 · Yi Yang1,2 Received: 23 April 2020 / Accepted: 12 September 2020 © Asian Pacific Association for the Study of the Liver 2020
Abstract Background and Aims Non-alcoholic fatty liver disease (NAFLD) and its complications has become an expanding health problem worldwide with limited therapeutic approaches. The current study was aiming to identify novel microRNA in the regulation of hepatic lipid metabolism in NAFLD. Approches and Results Systematic screening of microRNA expression by high-throughput small RNA sequencing demonstrated that microRNA 199a-5p (miR-199a-5p) was significantly upregulated in high fat diet-induced steatosis mouse model, with the most abundant expression in adipose tissue. MST1 was further identified as the target gene for miR-199a with specific recognition at the 3′ untranslated region with dural luciferase reporter assay. Delivery of miR-199a-5p with exosomes into mice aggravated liver lipid accumulation in hepatocytes, accompanied by down-regulation of hepatic MST1 expression and modulation of hepatic lipogenesis and lipolysis, including SREBP-1c, AMPK signaling cascades and the down-stream CPT1α and FASN. Conversely, administration of exosome containing anti-miR-199a-5p resulted in attenuated steotosis in mice fed on high fat diet. Importanly, miR-199a-5p-induced abnormal cellular lipid accumulation could be markedly reversed by overexpression of MST1. Conclusion miR-199a-5p might be an essentail regulator for hepatic lipid metabolism, possibly through its interction with MST1 and the subsequent signaling cascade. Thus, miR-199a-5p may serve as an important therapeutic target in the treatment of NAFLD. Keywords NAFLD · miR-199a-5p · Exosomes · MST1 Abbreviations NAFLD Non-alcoholic fatty liver disease NASH Non-alcoholic steatohepatitis MST1 Mammalian sterile 20-like kinase 1 Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12072-020-10096-0) contains supplementary material, which is available to authorized users. * Zhiwei Yang [email protected] * Yi Yang [email protected] 1
School of Basic Medical Sciences, Ningxia Medical University, Xingqing District, 692 Shengli St, Yinchuan 75004, China
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The Institute of Endocrinology, Ningxia Medical University, Yinchuan, China
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Second Affiliated Hospital, Ningxia Medical University, Yinchuan, China
FASN Fatty acid synthase EXO Exosomes ACC Acetyl-CoA carboxylase CPT-1α Carnitine palmitoyltransferase I α AMPK AMP-activated protein kinase PA Palmitic acid ORO Oil red O 4
Institute of Developmental Biology and Molecular Medicine and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
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