Yuhan Li1,2,3, Yansong Luan1,2, Jianning Li1,2, Hui Song1,2, Yan Li1,2, Hi Qi1, Bo Sun4, Peng Zhang4, Xianxian Wu3, Xing Liu3, Yanhui Yang1,2, Wufan Tao5, Lei Cai6, Zhiwei Yang7, Yi Yang8,9. 1. School of Basic Medical Sciences, Ningxia Medical University, Xingqing District, 692 Shengli St, Yinchuan, 75004, China. 2. The Institute of Endocrinology, Ningxia Medical University, Yinchuan, China. 3. Institute of Laboratory Animal Science (ILAS), Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS&PUMC), #5 Pan Jia Yuan Nan Li, Chaoyang Districe, Beijing, 100021, China. 4. Second Affiliated Hospital, Ningxia Medical University, Yinchuan, China. 5. Institute of Developmental Biology and Molecular Medicine and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China. 6. Department of Physiology, Cardiovascular Research Center, University of Kentucky, Lexington, KY, 40536, USA. 7. Institute of Laboratory Animal Science (ILAS), Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS&PUMC), #5 Pan Jia Yuan Nan Li, Chaoyang Districe, Beijing, 100021, China. yangzhiwei@cnilas.pumc.edu.cn. 8. School of Basic Medical Sciences, Ningxia Medical University, Xingqing District, 692 Shengli St, Yinchuan, 75004, China. yangyi0908666@163.com. 9. The Institute of Endocrinology, Ningxia Medical University, Yinchuan, China. yangyi0908666@163.com.
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.
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 steatosismouse 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.
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