摘要：
Recent studies have suggested that miR-590 may play critical roles in cardiovascular disease. This study was designed to determine the effects of miR-590 on lipoprotein lipase (LPL) expression and development of atherosclerosis in apolipoprotein E knockout (apoE(-/-)) mice and explore the potential mechanisms. En face analysis of the whole aorta revealed that miR-590 significantly decreased aortic atherosclerotic plaque size and lipid content in apoE (-/-) mice. Double immunofluorescence staining in cross-sections of the proximal aorta showed that miR-590 agomir reduced CD68 and LPL expression in macrophages in atherosclerotic lesions. MiR-590 agomir down-regulated LPL mRNA and protein expression as analyzed by RT-qPCR and western blotting analyses, respectively. Consistently, miR-590 decreased the expression of CD36 and scavenger receptor A1 (SRA1) mRNA and protein. High-performance liquid chromatography (HPLC) analysis confirmed that treatment with miR-590 agomir reduced lipid levels either in plasma orinabdominal cavity macrophages of apoE(-/-) mice. ELISA analysis showed that miR-590 agomir decreased plasma levels of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), monocyte chemotactic protein-1 (MCP-1), interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6). In contrast, treatment with miR-590 antagomir prevented or reversed these effects. Taken together, these results reveal a novel mechanism of miR-590 effects, and may provide new insights into the development of strategies for attenuating lipid accumulation and pro-inflammatory cytokine secretion.
摘要：
Melatonin is biosynthesized in the pineal gland and secreted into the bloodstream. Evidences indicate a role of melatonin in the regulation of glucose metabolism. The objective of this study was to investigate the effect of melatonin on insulin sensitivity in insulin resistant adipocytes. Following a preincubation with melatonin or vehicle for 30 min, insulin resistant cells of 3T3-L1 adipocytes were induced by palmitic acids (300 mu M, 6 h). Our results showed that palmitic acids inhibited both the basal and insulin-stimulated uptake of [H-3]-2-Deoxyglucose, down-regulated the levels of IRS-1 and GLUT-4. However, compared to the vehicle group, melatonin pre-treatment increased significantly the uptake of [H-3]-2-Deoxyglucose as well as the level of GLUT-4, and decreased phosphorylated IRS-1 (Ser307) although total IRS-1 did not change significantly. These data suggest that palmitic acids impair insulin signal via down-regulating the expressions of IRS-1 and GLUT-4; whereas melatonin can ameliorate insulin sensitivity by inhibiting Ser307 phosphorylation in IRS-1 and increasing GLUT-4 expressions in insulin resistant 3T3-L1 adipocytes. We conclude that melatonin regulates the insulin sensitivity and glucose homeostasis via inhibiting Ser-phosphorylation and improving function of IRS-1. (C) 2014 Elsevier Masson SAS. All rights reserved.
摘要：
Background: Accumulating evidence suggests that microRNA-590 (miR-590) has protective effects on cardiovascular diseases, but the mechanism is unknown. Interestingly, previous studies from our laboratory and others have shown that macrophage-derived lipoprotein lipase (LPL) might accelerate atherosclerosis by promoting lipid accumulation and inflammatory response. However, the regulation of LPL at the post-transcriptional level by microRNAs has not been fully understood. In this study, we explored whether miR-590 affects the expression of LPL and its potential subsequent effects on lipid accumulation and pro-inflammatory cytokine secretion in human THP-1 macrophages. Methods and results: Using bioinformatics analyses and dual-luciferase reporter assays, we found that miR-590 directly inhibited LPL protein and mRNA expression by targeting LPL 3'UTR. LPL Activity Assays showed that miR-590 reduced LPL activity in the culture media. Oil Red 0 staining and high-performance liquid chromatography assays showed that miR-590 had inhibitory effects on the lipid accumulation in human THP-1 macrophages. We also illustrated that miR-590 alleviated pro-inflammatory cytokine secretion in human THP-1 macrophages as measured by ELISA. With the method of small interfering RNA, we found that LPL siRNA can inhibit the miR-590 inhibitor-induced increase in lipid accumulation and secretion of pro-inflammatory cytokines in oxLDL-treated human THP-1 macrophages. Conclusions: MiR-590 attenuates lipid accumulation and pro-inflammatory cytokine secretion by targeting LPL gene in human THP-1 macrophages. Therefore, targeting miR-590 may offer a promising strategy to treat atherosclerotic cardiovascular diseases. (C) 2014 Elsevier B.V. and Societe francaise de biochimie et biologie Moleculaire (SFBBM). All rights reserved.
摘要：
Melatonin is synthesized and secreted mainly by the pineal gland in a circadian fashion, and it thus mediates endogenous circadian rhythms and influences other physiological functions. Both the G-protein coupled receptors MT1 (encoded by MTNR1A) and MT2 (encoded by MTNR1B) in mammals mediate the actions of melatonin. Evidence from in vivo and in vitro studies proved a key role of melatonin in the regulation of glucose metabolism and the pathogenesis of diabetes, as further confirmed by the recent studies of human genetic variants of MTNR1B. Remarkably, it was also suggested that genetic variations within MTNR1B disordered beta-cells function directly, i.e. insulin secretion. This indicated the functional link between MT2 and T2D risk at the protein level, and it may represent the prevailing pathomechanism for how impaired melatonin signaling causes metabolic disorders and increases the T2D risk lt is speculated that melatonin and its receptors may be a new therapeutic avenue in diabetes. (C) 2014 Elsevier B.V. All rights reserved.
摘要：
Lipoprotein lipase (LPL) is a key enzyme in lipid metabolism and responsible for catalyzing lipolysis of triglycerides in lipoproteins. LPL is produced mainly in adipose tissue, skeletal and heart muscle, as well as in macrophage and other tissues. After synthesized, it is secreted and translocated to the vascular lumen. LPL expression and activity are regulated by a variety of factors, such as transcription factors, interactive proteins and nutritional state through complicated mechanisms. LPL with different distributions may exert distinct functions and have diverse roles in human health and disease with close association with atherosclerosis. It may pose a pro-atherogenic or an anti-atherogenic effect depending on its locations. In this review, we will discuss its gene, protein, synthesis, transportation and biological functions, and then focus on its regulation and relationship with atherosclerosis and potential underlying mechanisms. The goal of this review is to provide basic information and novel insight for further studies and therapeutic targets. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
期刊：
Cell Biochemistry and Biophysics,2013年67(3):1239-1248 ISSN：1085-9195
通讯作者：
Xu, Gui-lian
作者机构：
[Yin, Wei-dong; Feng, Shao-long; Cao, Zhao-hui] Univ South China, Sch Pharm & Life Sci, Hengyang 421001, Peoples R China.;[Xu, Gui-lian; Cao, Zhao-hui] Third Mil Med Univ, Dept Immunol, Chongqing 400038, Peoples R China.;[Zheng, Quan-you; Zhang, Ke-qin; Cao, Zhao-hui] Third Mil Med Univ, Inst Surg Res, Daping Hosp, Dept Urol, Chongqing 400042, Peoples R China.
通讯机构：
[Xu, Gui-lian] T;Third Mil Med Univ, Dept Immunol, Chongqing 400038, Peoples R China.
作者机构：
[She, M.-H.; Jiang, W.-Y.; Hu, X.-B.; Yin, W.-D.] Dept. of Biochemistry and Molecular Biology, School of Life Sciences and Technology, University of South China, Hengyang Hunan 421001, China;[Yang, S.-H.] First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China;[Laudon, M.] Drug Discovery, Neurim Pharmaceuticals Lad, Tel-Aviv, Israel
作者机构：
[Wang, P.-P.] Institute of Cardiovascular Diseases, University of South China, Hengyang Hunan 421001, China;[She, M.-H.] Dept. of Biochemistry and Molecular Biology, University of South China, Hengyang Hunan 421001, China;[Laudon, M.] Neurim Pharmaceuticals Ltd., Israel;[Yin, W.-D.] Institute of Cardiovascular Diseases, University of South China, Hengyang Hunan 421001, China, Dept. of Biochemistry and Molecular Biology, University of South China, Hengyang Hunan 421001, China
关键词：
胰岛素抵抗;甘油三酯;脂肪组织甘油三酯酶;激素敏感性脂肪酶
摘要：
目的探讨脂肪组织甘油三酯酶(adipose triglyceride lipase,ATGL)及激素敏感性脂肪酶(hormone-sensitive lipase,HSL)在褪黑素非选择性受体激动剂Neu-p11改善高糖高胰岛素(high glucose and insulin,HGI)诱导的3T3-L1脂肪细胞胰岛素抵抗(insulin resistance,IR)中的作用及机制.方法培养3T3-L1脂肪细胞,HGI诱导IR模型.以葡萄糖消耗量及细胞内甘油三酯(triglyceride,TG)定量测定作为检测指标,Western blot检测蛋白水平的表达情况.结果HGI孵育减少脂肪细胞葡萄糖摄取,促进细胞内TG积聚,同时伴有ATGL及HSL的蛋白表达下调.Neu-p11干预逆转了HGI对脂肪细胞的作用效应,而MT2竞争性拮抗剂luzindole却拮抗了Neu-p11的上述效应.结论Neu-p11以MT2受体依赖性方式抑制IR脂肪细胞TG沉积,可能与其上调ATGL、HSL蛋白的表达,促进TG水解相关.
