β细胞中PTHrP的过表达揭示了内质网应激的关键作用。

IF 3.3 3区 医学 Q2 ENDOCRINOLOGY & METABOLISM
Ibiagbani M Max-Harry, Nida Ajmal, Palwasha Khan, Landen E Davis, Waleed J Hashmi, Noriko Kantake, Kathryn L Corbin, Thomas J Rosol, Craig S Nunemaker
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引用次数: 0

摘要

注射甲状旁腺激素相关蛋白(PTHrP)已被证明可增加小鼠胰岛素含量和分泌。PTHrP还能增加β细胞的质量和增殖。然而,这些作用的机制尚不清楚,研究尚未检查转录组中的PTHrP。在这项研究中,我们用全长PTHrP或DSred载体瞬时转染了小鼠β细胞系(MIN6)。测量胰岛素含量和葡萄糖刺激胰岛素分泌,并收集细胞在20mM葡萄糖中孵育后的RNA。结果表明,PTHrP过表达可提高胰岛素含量及胰岛素分泌低糖与高糖比值(刺激指数)。rna测序结果显示,PTHrP过表达下调了许多内质网应激相关基因,如Hspa40、Dnajc3和Xbp1。在富集的KEGG通路中,内质网应激基因通路下调幅度最大,而蛋白质合成所需氨基酸的生物合成通路上调幅度最大。这些途径表明蛋白质生物合成速率增加。qPCR支持多个内质网应激基因(Xbp1, Bax, Bip)的rna测序结果。转染PTHrP的MIN6细胞也具有较低的胰岛素原与胰岛素比值,表明PTHrP增强了内质网中的胰岛素加工。我们的工作假设是PTHrP增加胰岛素产生和内质网效率,这与MIN6细胞中胰岛素含量增加、胰岛素原与胰岛素比值降低和内质网应激标志物降低的观察结果一致。总之,我们的研究结果表明PTHrP在β细胞内质网中的作用是未知的,这可能对提高胰岛素的产生有治疗意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Overexpression of PTHrP in β Cells Reveals Key Effects on Endoplasmic Reticulum Stress.

Administration of parathyroid hormone-related protein (PTHrP) has been shown to increase insulin content and secretion in mice. PTHrP also increases β-cell mass and proliferation. However, the mechanisms for these effects are unknown, and investigations have yet to examine PTHrP in the transcriptome. In this study, we transiently transfected a mouse β-cell line (MIN6) with either full-length PTHrP or DSred vector. Insulin content and glucose-stimulated insulin secretion were measured, and RNA from the cells after incubating in 20 mM glucose was collected. The results showed that PTHrP overexpression increased insulin content and the ratio of insulin secretion between low and high glucose (stimulation index). RNA sequencing showed that PTHrP overexpression downregulated many genes associated with responses to endoplasmic reticulum (ER) stress such as Hspa40, Dnajc3, and Xbp1. Among enriched Kyoto Encyclopedia of Genes and Genomes pathways, the ER stress gene pathway was the most strongly downregulated by far, and the most upregulated pathway was for biosynthesis of amino acids required for protein synthesis. These pathways suggest increased rates of protein biosynthesis. Quantitative polymerase chain reaction supported RNA-sequencing results for several ER stress genes (Xbp1, Bax, Bip). MIN6 cells transfected with PTHrP also had lower proinsulin-to-insulin ratio, indicating that PTHrP enhanced insulin processing in the ER. Our working hypothesis is that PTHrP augments insulin production and ER efficiency, which is consistent with observations of increased insulin content, decreased proinsulin-to-insulin ratio and reduced ER stress markers in MIN6 cells. In conclusion, our findings suggest a previously unknown role for PTHrP in β-cell endoplasmic reticulum, which may have therapeutic implications for enhancing insulin production.

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来源期刊
Endocrinology
Endocrinology 医学-内分泌学与代谢
CiteScore
8.10
自引率
4.20%
发文量
195
审稿时长
2-3 weeks
期刊介绍: The mission of Endocrinology is to be the authoritative source of emerging hormone science and to disseminate that new knowledge to scientists, clinicians, and the public in a way that will enable "hormone science to health." Endocrinology welcomes the submission of original research investigating endocrine systems and diseases at all levels of biological organization, incorporating molecular mechanistic studies, such as hormone-receptor interactions, in all areas of endocrinology, as well as cross-disciplinary and integrative studies. The editors of Endocrinology encourage the submission of research in emerging areas not traditionally recognized as endocrinology or metabolism in addition to the following traditionally recognized fields: Adrenal; Bone Health and Osteoporosis; Cardiovascular Endocrinology; Diabetes; Endocrine-Disrupting Chemicals; Endocrine Neoplasia and Cancer; Growth; Neuroendocrinology; Nuclear Receptors and Their Ligands; Obesity; Reproductive Endocrinology; Signaling Pathways; and Thyroid.
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