Circulating extracellular vesicle-derived miR-1299 disrupts hepatic glucose homeostasis by targeting the STAT3/FAM3A axis in gestational diabetes mellitus

作者全名："Chen, Xuyang; Tao, Xinyi; Wang, Min; Cannon, Richard D.; Chen, Bingnan; Yu, Xinyang; Qi, Hongbo; Saffery, Richard; Baker, Philip N.; Zhou, Xiaobo; Han, Ting-Li; Zhang, Hua"

作者地址："[Chen, Xuyang; Tao, Xinyi; Wang, Min; Chen, Bingnan; Yu, Xinyang; Zhang, Hua] Chongqing Med Univ, Affiliated Hosp 1, Dept Obstet & Gynaecol, 1 Youyi Rd, Chongqing 400016, Peoples R China; [Chen, Xuyang; Tao, Xinyi; Wang, Min; Chen, Bingnan; Yu, Xinyang; Qi, Hongbo; Zhou, Xiaobo; Han, Ting-Li; Zhang, Hua] Chongqing Med Univ, Chongqing Key Lab Maternal & Fetal Med, Chongqing, Peoples R China; [Cannon, Richard D.] Univ Otago, Sir John Walsh Res Inst, Fac Dent, Dept Oral Sci, Dunedin, New Zealand; [Qi, Hongbo] Chongqing Med Univ, Women & Childrens Hosp, Chongqing, Peoples R China; [Saffery, Richard] Royal Childrens Hosp, Murdoch Childrens Res Inst, Mol Immun, Melbourne, Australia; [Baker, Philip N.] Univ Leicester, Coll Life Sci, Leicester, England; [Zhou, Xiaobo] Chongqing Med Univ, Affiliated Hosp 1, Dept Ctr Reprod Med, 1 Youyi Rd, Chongqing 400016, Peoples R China; [Han, Ting-Li] Chongqing Med Univ, Affiliated Hosp 2, Dept Gynecol & Obstet, 74 Linjiang Rd, Chongqing 400010, Peoples R China"

通信作者："Zhang, H (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Obstet & Gynaecol, 1 Youyi Rd, Chongqing 400016, Peoples R China.; Zhou, XB; Han, TL; Zhang, H (通讯作者)，Chongqing Med Univ, Chongqing Key Lab Maternal & Fetal Med, Chongqing, Peoples R China.; Zhou, XB (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Ctr Reprod Med, 1 Youyi Rd, Chongqing 400016, Peoples R China.; Han, TL (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Gynecol & Obstet, 74 Linjiang Rd, Chongqing 400010, Peoples R China."

来源：JOURNAL OF NANOBIOTECHNOLOGY

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001297034400001

JCR分区：Q1

影响因子：10.2

年份：2024

卷号：22

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Gestational diabetes mellitus; Extracellular vesicles; Insulin resistance; MiR-1299/STAT3/FAM3A

摘要："BackgroundExtracellular vesicles (EVs) are membrane-enclosed structures containing lipids, proteins, and RNAs that play a crucial role in cell-to-cell communication. However, the precise mechanism through which circulating EVs disrupt hepatic glucose homeostasis in gestational diabetes mellitus (GDM) remains unclear.ResultsCirculating EVs isolated from human plasma were co-cultured with mammalian liver cells to investigate the potential induction of hepatic insulin resistance by GDM-EVs using glucose output assays, Seahorse assays, metabolomics, fluxomics, qRT-PCR, bioinformatics analyses, and luciferase assays. Our findings demonstrated that hepatocytes exposed to GDM-EVs exhibited increased gluconeogenesis, attenuated energy metabolism, and upregulated oxidative stress. Particularly noteworthy was the discovery of miR-1299 as the predominant miRNA in GDM-EVs, which directly targeting the 3 '-untranslated regions (UTR) of STAT3. Our experiments involving loss- and gain-of-function revealed that miR-1299 inhibits the insulin signaling pathway by regulating the STAT3/FAM3A axis, resulting in increased insulin resistance through the modulation of mitochondrial function and oxidative stress in hepatocytes. Moreover, experiments conducted in vivo on mice inoculated with GDM-EVs confirmed the development of glucose intolerance, insulin resistance, and downregulation of STAT3 and FAM3A.ConclusionsThese results provide insights into the role of miR-1299 derived from circulating GDM-EVs in the progression of insulin resistance in hepatic cells via the STAT3/FAM3A axis and downstream metabolic reprogramming."

基金机构：Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases

基金资助正文：The authors thank all the study participants and all collaborators for data collection. The authors are grateful for the support provided by The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases. We also would like to thank Figdraw (www.figdraw.com).