Irisin Promotes Human Umbilical Vein Endothelial Cell Proliferation through the ERK Signaling Pathway and Partly Suppresses High Glucose-Induced Apoptosis

Song, Haibo; Wu, Fei; Zhang, Yuan; Wang, Fang; Jiang, Miao; Wang, Zhongde; Zhang, Mingxiang; Li, Shiwu; Yang, Lijun; Wang, Xing Li; Cui, Taixing; Tang, Dongqi

doi:10.1371/journal.pone.0110273

Cited by 107 publications

(109 citation statements)

References 27 publications

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“…Inhibition of p38 mitogen-activated protein kinase or Erk abolished the upregulatory effect of irisin on Ucp1 expression (31). This signaling pathway was also shown in human umbilical vein endothelial cells (32). However, we did not find the Erk pathway nor the Akt and JNK pathways changed by irisin treatment in hepatocytes.…”

Section: Discussionmentioning

confidence: 44%

Irisin Is Regulated by CAR in Liver and Is a Mediator of Hepatic Glucose and Lipid Metabolism

Shen

Liu

et al. 2016

Molecular Endocrinology

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Irisin, a hormone proteolytically processed from fibronectin type III domain-containing protein 5 (FNDC5), has been reported to induce the browning of sc adipocytes by increasing the level of uncoupling protein 1. In this study, we showed that activation of the nuclear receptor constitutive androstane receptor induced FNDC5 mRNA expression in the liver and increased the circulating level of irisin in mice. FNDC5/irisin is a direct transcriptional target of constitutive androstane receptor. Hepatic-released irisin functioned as a paracrine/autocrine factor that inhibited lipogenesis and gluconeogenesis via the Adenosine 5'-monophosphate (AMP)-activated protein kinase pathway. Adenovirus-overexpressed irisin improved hepatic steatosis and insulin resistance in genetic-induced obese mice. Irisin transgenic mice were also protected against high-fat diet-induced obesity and insulin resistance. In conclusion, our results reveal a novel pathway in regulating FNDC5/irisin expression and identify a physiological role for this hepatic hormone in glucose and lipid homeostasis.

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Section: Discussionmentioning

confidence: 44%

Irisin Is Regulated by CAR in Liver and Is a Mediator of Hepatic Glucose and Lipid Metabolism

Shen

Liu

et al. 2016

Molecular Endocrinology

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“…For example, the rs145204276 located in the promoter region of GAS5 has been reported to be an endogenous competing RNA of miR-21 [23][24][25]. Also, PDCD4 is believed to play a critical function in the pathogenesis of atherosclerosis by modulating the apoptosis of vascular endothelial cells [26,27], while our in-silicon analysis also found that miR-21 virtually targeted PDCD4. In this study, we aimed to explore the role of GAS5, miR-21, and its target genePDCD4, in the control of apoptosis of endothelial cells.…”

Section: Introductionmentioning

confidence: 52%

Association Between the Deletion Allele of Ins/Del Polymorphism (Rs145204276) in the Promoter Region of GAS5 with the Risk of Atherosclerosis

Shen

Qiang

2018

Cell Physiol Biochem

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Background/Aims: LncRNA is a growth arrest-specific transcript 5 (GAS5) with tumor suppressor activities in some cancers, but its role in atherosclerosis is unclear. Methods: Bioinformatics algorithm analysis was utilized to search the target of GAS5 and miR-21, followed by luciferase assay to confirm these targets. Real-time PCR and western-blot were utilized to verify the connection among GAS5, miR-21 and Programmed cell death 4 (PDCD4). MTT assay and flow cytometry analysis were performed to explore the mechanism of GAS5 in the regulation of atherosclerosis. Results: GAS5 directly targets miR-21 and functions as a competing endogenous RNA to suppress miR-21 expression. We also observed that rs145204276 polymorphism, including INS/INS and DEL/DEL, on GAS5 promoter increased transcription activity of GAS5, but the presence of rs145204276 DEL/DEL allele significantly promoted the transcription of GAS5 promoter compared with rs145204276 INS/INS allele. PDCD4 was predicted as a direct target gene of miR-21 with a binding site on PDCD4 3’UTR. It was further confirmed by luciferase assay that miR-21 significantly reduced the luciferase activity of wild-type PDCD4 3’UTR but not that of mutant PDCD4 3’UTR. In addition, high glucose significantly inhibited the growth rate of EC genotyped as DEL/DEL or INS/ INS, and apparently promoted the apoptotic rate of either DEL/DEL or INS/INS genotype ECs. Furthermore, the effect of high glucose was stronger in the INS/INS group, while the expression of GAS5 was dramatically upregulated with the presence of GAS5 DEL/DEL, while GAS5 positively regulated PDCD4 expression via inhibiting miR-21 expression. GAS5 siRNA and miR-21 mimics significantly decreased GAS5 and PDCD4 expressions, and the inhibitory effects of GAS5 siRNA or miR-21 mimics on GAS5 and PDCD4 expressions in the INS/INS group was stronger. Moreover, GAS5 siRNA and miR-21 mimics remarkably triggered cells proliferation and suppressed cell apoptosis, and the inhibition effects of GAS5 siRNA or miR-21 mimics on either cell viability and apoptosis in the INS/INS group was stronger. In this study, we enrolled 1,306 subjects with or without atherosclerosis and found that the INS/DEL or DEL/DEL genotypes significantly decreased the risk of atherosclerosis compared with the ins/ins genotype (adjusted odds ratio: 0.74 and 0.40, respectively). Conclusion: In summary, rs145204276 was associated with the risk of atherosclerosis by affecting the proliferation and apoptosis of endothelial cells via regulating the GAS5/miR-21/PDCD4 signaling pathway.

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“…Recent studies have demonstrated that irisin can promote cell proliferation and protect cells from high-glucose-induced damage[3]. However, the effects of irisin on pancreatic β cells are still unclear.…”

Section: Discussionmentioning

confidence: 99%

Effects and underlying mechanisms of irisin on the proliferation and apoptosis of pancreatic β cells

Liu

et al. 2017

PLoS ONE

107

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Pancreatic β cell dysfunction and reduction due to glucose toxicity play a crucial role in the development of type 2 diabetes mellitus (T2DM). Irisin, a novel exercise-induced myokine, reduces obesity, improves insulin resistance and lowers blood glucose by promoting the browning of white adipose tissue, thereby enhancing thermogenesis and increasing energy expenditure. Recent studies have reported that irisin promotes cell proliferation and protects cells from apoptosis. However, the effects of irisin on pancreatic β cells are unknown. Thus, the aim of this study was to investigate the effects and the potential underlying mechanisms of irisin on pancreatic β cell proliferation and apoptosis induced by high glucose. Both in vitro (INS-1 cells) and in vivo (a T2DM rat model) experiments were conducted. Irisin significantly increased the proliferation of INS-1 cells, with the most significant effect observed at 24 h with 100 ng/ml irisin. Irisin also promoted INS-1 cell proliferation via the ERK and p38 MAPK signaling pathways, protected the cells from high-glucose-induced apoptosis by regulating the expression of caspases, Bad, Bax, Bcl-2 and Bcl-xl, and improved pancreatic β cell function. Irisin significantly reduced the body weight and blood glucose values and increased the serum insulin levels of the diabetic rats. An oral glucose tolerance test (OGTT) indicated that irisin also improved the glucose tolerance of T2DM rats. Together, these findings suggest that irisin may have applications in the prevention and treatment of T2DM because of its protective effect on the secretion of pancreatic β cells.

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Irisin Promotes Human Umbilical Vein Endothelial Cell Proliferation through the ERK Signaling Pathway and Partly Suppresses High Glucose-Induced Apoptosis

Cited by 107 publications

References 27 publications

Irisin Is Regulated by CAR in Liver and Is a Mediator of Hepatic Glucose and Lipid Metabolism

Irisin Is Regulated by CAR in Liver and Is a Mediator of Hepatic Glucose and Lipid Metabolism

Association Between the Deletion Allele of Ins/Del Polymorphism (Rs145204276) in the Promoter Region of GAS5 with the Risk of Atherosclerosis

Effects and underlying mechanisms of irisin on the proliferation and apoptosis of pancreatic β cells

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