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Hepatic Sam68 Regulates Systemic Glucose Homeostasis and Insulin Sensitivity

文献类型：期刊论文

作者Qiao, Aijun2,3,4; Ma, Wenxia4; Jiang, Ying4; Han, Chaoshan4; Yan, Baolong4; Zhou, Junlan1; Qin, Gangjian1,4
刊名INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
出版日期2022-10-01
卷号23期号:19页码:14
关键词Sam68 hepatocytes gluconeogenesis high-fat diet diabetes CRTC2 insulin sensitivity glucagon glucose metabolism protein-protein interaction
DOI10.3390/ijms231911469
通讯作者Qiao, Aijun(qiaoaijun@simm.ac.cn) ; Qin, Gangjian(gqin@uab.edu)
英文摘要Hepatic glucose production (HGP) is an important component of glucose homeostasis, and deregulated HGP, particularly through gluconeogenesis, contributes to hyperglycemia and pathology of type-2 diabetes (T2D). It has been shown that the gluconeogenic gene expression is governed primarily by the transcription factor cAMP-response element (CRE)-binding protein (CREB) and its coactivator, CREB-regulated transcriptional coactivator 2 (CRTC2). Recently, we have discovered that Sam68, an adaptor protein and Src kinase substrate, potently promotes hepatic gluconeogenesis by promoting CRTC2 stability; however, the detailed mechanisms remain unclear. Here we show that in response to glucagon, Sam68 increases CREB/CRTC2 transactivity by interacting with CRTC2 in the CREB/CRTC2 complex and occupying the CRE motif of promoters, leading to gluconeogenic gene expression and glucose production. In hepatocytes, glucagon promotes Sam68 nuclear import, whereas insulin elicits its nuclear export. Furthermore, ablation of Sam68 in hepatocytes protects mice from high-fat diet (HFD)-induced hyperglycemia and significantly increased hepatic and peripheral insulin sensitivities. Thus, hepatic Sam68 potentiates CREB/CRTC2-mediated glucose production, contributes to the pathogenesis of insulin resistance, and may serve as a therapeutic target for T2D.
WOS关键词RNA-BINDING PROTEIN ; TRANSCRIPTIONAL COACTIVATOR ; EXPRESSION ; TORC2 ; GLUCONEOGENESIS ; INHIBITION ; ACTIVATION ; CRTC2 ; SRC
资助项目American Diabetes Association[1-15-BS-148] ; American Heart Association[19TPA34910227] ; American Heart Association[19CDA34630052]
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
出版者MDPI
WOS记录号WOS:000867760800001
源URL[http://119.78.100.183/handle/2S10ELR8/302778]  
专题中国科学院上海药物研究所
通讯作者Qiao, Aijun; Qin, Gangjian
作者单位1.Northwestern Univ, Feinberg Sch Med, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USA
2.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
4.Univ Alabama Birmingham, Sch Med & Sch Engn, Dept Biomed Engn, Birmingham, AL 35294 USA
推荐引用方式
GB/T 7714		 Qiao, Aijun,Ma, Wenxia,Jiang, Ying,et al. Hepatic Sam68 Regulates Systemic Glucose Homeostasis and Insulin Sensitivity[J]. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,2022,23(19):14.
APA Qiao, Aijun.,Ma, Wenxia.,Jiang, Ying.,Han, Chaoshan.,Yan, Baolong.,...&Qin, Gangjian.(2022).Hepatic Sam68 Regulates Systemic Glucose Homeostasis and Insulin Sensitivity.INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,23(19),14.
MLA Qiao, Aijun,et al."Hepatic Sam68 Regulates Systemic Glucose Homeostasis and Insulin Sensitivity".INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 23.19(2022):14.

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来源：上海药物研究所

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