• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

棕榈酸盐会损害胰岛功能，而二十碳五烯酸则通过调节胰岛中的固醇调节元件结合蛋白1c（SREBP-1c）来恢复胰岛素分泌。

Palmitate impairs and eicosapentaenoate restores insulin secretion through regulation of SREBP-1c in pancreatic islets.

作者信息

Kato Toyonori, Shimano Hitoshi, Yamamoto Takashi, Ishikawa Mayumi, Kumadaki Shin, Matsuzaka Takashi, Nakagawa Yoshimi, Yahagi Naoya, Nakakuki Masanori, Hasty Alyssa H, Takeuchi Yoshinori, Kobayashi Kazuto, Takahashi Akimitsu, Yatoh Shigeru, Suzuki Hiroaki, Sone Hirohito, Yamada Nobuhiro

机构信息

Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.

出版信息

Diabetes. 2008 Sep;57(9):2382-92. doi: 10.2337/db06-1806. Epub 2008 May 5.

DOI:10.2337/db06-1806
PMID:18458149
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2518489/
Abstract

OBJECTIVE

Chronic exposure to fatty acids causes beta-cell failure, often referred to as lipotoxicity. We investigated its mechanisms, focusing on contribution of SREBP-1c, a key transcription factor for lipogenesis.

RESEARCH DESIGN AND METHODS

We studied in vitro and in vivo effects of saturated and polyunsaturated acids on insulin secretion, insulin signaling, and expression of genes involved in beta-cell functions. Pancreatic islets isolated from C57BL/6 control and SREBP-1-null mice and adenoviral gene delivery or knockdown systems of related genes were used.

RESULTS

Incubation of C57BL/6 islets with palmitate caused inhibition of both glucose- and potassium-stimulated insulin secretion, but addition of eicosapentaenoate (EPA) restored both inhibitions. Concomitantly, palmitate activated and EPA abolished both mRNA and nuclear protein of SREBP-1c, accompanied by reciprocal changes of SREBP-1c target genes such as insulin receptor substrate-2 (IRS-2) and granuphilin. These palmitate-EPA effects on insulin secretion were abolished in SREBP-1-null islets. Suppression of IRS-2/Akt pathway could be a part of the downstream mechanism for the SREBP-1c-mediated insulin secretion defect because adenoviral constitutively active Akt compensated it. Uncoupling protein-2 (UCP-2) also plays a crucial role in the palmitate inhibition of insulin secretion, as confirmed by knockdown experiments, but SREBP-1c contribution to UCP-2 regulation was partial. The palmitate-EPA regulation of insulin secretion was similarly observed in islets from C57BL/6 mice pretreated with dietary manipulations. Furthermore, administration of EPA to diabetic KK-Ay mice ameliorated impairment of insulin secretion in their islets.

CONCLUSIONS

SREBP-1c plays a dominant role in palmitate-mediated insulin secretion defect, and EPA prevents it through SREBP-1c inhibition, implicating a therapeutic potential for treating diabetes related to lipotoxicity.

摘要

目的

长期暴露于脂肪酸会导致β细胞功能衰竭，通常称为脂毒性。我们研究了其机制，重点关注脂肪生成的关键转录因子SREBP-1c的作用。

研究设计与方法

我们研究了饱和脂肪酸和多不饱和脂肪酸对胰岛素分泌、胰岛素信号传导以及参与β细胞功能的基因表达的体外和体内效应。使用从C57BL/6对照小鼠和SREBP-1基因敲除小鼠分离的胰岛以及相关基因的腺病毒基因递送或敲低系统。

结果

用棕榈酸孵育C57BL/6胰岛会抑制葡萄糖和钾刺激的胰岛素分泌，但添加二十碳五烯酸（EPA）可恢复这两种抑制作用。同时，棕榈酸激活而EPA消除了SREBP-1c的mRNA和核蛋白，伴随着SREBP-1c靶基因如胰岛素受体底物-2（IRS-2）和颗粒体蛋白的相反变化。这些棕榈酸-EPA对胰岛素分泌的作用在SREBP-1基因敲除的胰岛中被消除。IRS-2/Akt途径的抑制可能是SREBP-1c介导的胰岛素分泌缺陷的下游机制的一部分，因为腺病毒组成型活性Akt可以补偿它。解偶联蛋白-2（UCP-2）在棕榈酸抑制胰岛素分泌中也起关键作用，敲低实验证实了这一点，但SREBP-1c对UCP-2调节的作用是部分的。在经过饮食处理的C57BL/6小鼠的胰岛中也观察到了棕榈酸-EPA对胰岛素分泌的调节作用。此外，给糖尿病KK-Ay小鼠施用EPA可改善其胰岛中胰岛素分泌的损伤。

结论

SREBP-1c在棕榈酸介导的胰岛素分泌缺陷中起主导作用，EPA通过抑制SREBP-1c来预防这种缺陷，这意味着在治疗与脂毒性相关的糖尿病方面具有治疗潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40aa/2518489/2c41147df179/zdb0080853690008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40aa/2518489/70e75a64c535/zdb0080853690001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40aa/2518489/a6f810b63b6b/zdb0080853690002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40aa/2518489/b79456f46a60/zdb0080853690003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40aa/2518489/139eac38f6a5/zdb0080853690004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40aa/2518489/bf1f350f4a5a/zdb0080853690005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40aa/2518489/faa97b242c71/zdb0080853690006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40aa/2518489/e903d4c7d7da/zdb0080853690007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40aa/2518489/2c41147df179/zdb0080853690008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40aa/2518489/70e75a64c535/zdb0080853690001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40aa/2518489/a6f810b63b6b/zdb0080853690002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40aa/2518489/b79456f46a60/zdb0080853690003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40aa/2518489/139eac38f6a5/zdb0080853690004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40aa/2518489/bf1f350f4a5a/zdb0080853690005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40aa/2518489/faa97b242c71/zdb0080853690006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40aa/2518489/e903d4c7d7da/zdb0080853690007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40aa/2518489/2c41147df179/zdb0080853690008.jpg

相似文献

1
Palmitate impairs and eicosapentaenoate restores insulin secretion through regulation of SREBP-1c in pancreatic islets.棕榈酸盐会损害胰岛功能，而二十碳五烯酸则通过调节胰岛中的固醇调节元件结合蛋白1c（SREBP-1c）来恢复胰岛素分泌。
Diabetes. 2008 Sep;57(9):2382-92. doi: 10.2337/db06-1806. Epub 2008 May 5.
2
Sterol regulatory element-binding protein-1c and pancreatic beta-cell dysfunction.固醇调节元件结合蛋白-1c与胰腺β细胞功能障碍
Diabetes Obes Metab. 2007 Nov;9 Suppl 2:133-9. doi: 10.1111/j.1463-1326.2007.00779.x.
3
Long-Term Exposure of Pancreatic β-Cells to Palmitate Results in SREBP-1C-Dependent Decreases in GLP-1 Receptor Signaling via CREB and AKT and Insulin Secretory Response.胰腺β细胞长期暴露于棕榈酸会导致通过CREB和AKT的GLP-1受体信号传导以及胰岛素分泌反应以SREBP-1C依赖性方式降低。
Endocrinology. 2016 Jun;157(6):2243-58. doi: 10.1210/en.2015-2003. Epub 2016 Apr 1.
4
Granuphilin is activated by SREBP-1c and involved in impaired insulin secretion in diabetic mice.颗粒亲和素由固醇调节元件结合蛋白-1c激活，并参与糖尿病小鼠胰岛素分泌受损的过程。
Cell Metab. 2006 Aug;4(2):143-54. doi: 10.1016/j.cmet.2006.06.009.
5
Sterol regulatory element-binding protein-1c knockdown protected INS-1E cells from lipotoxicity.固醇调节元件结合蛋白-1c 敲低可保护 INS-1E 细胞免受脂毒性。
Diabetes Obes Metab. 2010 Jan;12(1):35-46. doi: 10.1111/j.1463-1326.2009.01093.x. Epub 2009 Sep 16.
6
Transcriptional co-activator peroxisome proliferator-activated receptor (PPAR)gamma co-activator-1beta is involved in the regulation of glucose-stimulated insulin secretion in INS-1E cells.转录共激活因子过氧化物酶体增殖物激活受体（PPAR）γ共激活因子-1β参与INS-1E细胞中葡萄糖刺激的胰岛素分泌调节。
J Mol Med (Berl). 2009 Mar;87(3):299-306. doi: 10.1007/s00109-008-0425-0. Epub 2008 Dec 11.
7
Role of uncoupling protein-2 up-regulation and triglyceride accumulation in impaired glucose-stimulated insulin secretion in a beta-cell lipotoxicity model overexpressing sterol regulatory element-binding protein-1c.在过表达固醇调节元件结合蛋白-1c的β细胞脂毒性模型中，解偶联蛋白-2上调和甘油三酯积累在葡萄糖刺激的胰岛素分泌受损中的作用
Endocrinology. 2004 Aug;145(8):3566-77. doi: 10.1210/en.2003-1602. Epub 2004 Apr 1.
8
SREBP-1c, Pdx-1, and GLP-1R involved in palmitate-EPA regulated glucose-stimulated insulin secretion in INS-1 cells.SREBP-1c、Pdx-1 和 GLP-1R 参与软脂酸-EPA 调节的 INS-1 细胞葡萄糖刺激的胰岛素分泌。
J Cell Biochem. 2010 Oct 15;111(3):634-42. doi: 10.1002/jcb.22750.
9
Repression of sterol regulatory element-binding protein 1-c is involved in the protective effects of exendin-4 in pancreatic β-cell line.固醇调节元件结合蛋白 1-c 的抑制参与了 exendin-4 对胰岛β细胞系的保护作用。
Mol Cell Endocrinol. 2012 Oct 15;362(1-2):242-52. doi: 10.1016/j.mce.2012.07.004. Epub 2012 Jul 17.
10
Silibinin protects β cells from glucotoxicity through regulation of the Insig-1/SREBP-1c pathway.水飞蓟宾通过调节Insig-1/SREBP-1c信号通路保护β细胞免受糖毒性。
Int J Mol Med. 2014 Oct;34(4):1073-80. doi: 10.3892/ijmm.2014.1883. Epub 2014 Aug 8.

引用本文的文献

1
Marine N-3 Fatty Acids Mitigate Hyperglycemia in Prediabetes by Improving Muscular Glucose Transporter 4 Translocation and Glucose Homeostasis.海洋n-3脂肪酸通过改善肌肉葡萄糖转运蛋白4易位和葡萄糖稳态减轻糖尿病前期的高血糖症。
Research (Wash D C). 2025 Apr 29;8:0683. doi: 10.34133/research.0683. eCollection 2025.
2
Dietary alpha-linolenic acid supplementation enhances semen quality, antioxidant capacity, and sperm survival in aging breeder roosters.日粮补充α-亚麻酸可提高老龄种公鸡的精液质量、抗氧化能力和精子存活率。
Poult Sci. 2024 Dec;103(12):104252. doi: 10.1016/j.psj.2024.104252. Epub 2024 Aug 23.
3
Integrating Mendelian randomization and single-cell RNA sequencing to identify therapeutic targets of baicalin for type 2 diabetes mellitus.

本文引用的文献

1
Granuphilin is activated by SREBP-1c and involved in impaired insulin secretion in diabetic mice.颗粒亲和素由固醇调节元件结合蛋白-1c激活，并参与糖尿病小鼠胰岛素分泌受损的过程。
Cell Metab. 2006 Aug;4(2):143-54. doi: 10.1016/j.cmet.2006.06.009.
2
Glucose regulates Foxo1 through insulin receptor signaling in the pancreatic islet beta-cell.葡萄糖通过胰岛β细胞中的胰岛素受体信号传导调节Foxo1。
Diabetes. 2006 Jun;55(6):1581-91. doi: 10.2337/db05-0678.
3
[Contribution of free fatty acids to impairment of insulin secretion and action. mechanism of beta-cell lipotoxicity].
整合孟德尔随机化和单细胞RNA测序以鉴定黄芩苷治疗2型糖尿病的靶点
Front Pharmacol. 2024 Jul 26;15:1403943. doi: 10.3389/fphar.2024.1403943. eCollection 2024.
4
Epigallocatechin gallate attenuated high glucose-induced pancreatic beta cell dysfunction by modulating DRP1-mediated mitochondrial apoptosis pathways.没食子儿茶素没食子酸酯通过调节 DRP1 介导的线粒体凋亡通路减轻高糖诱导的胰岛β细胞功能障碍。
Sci Rep. 2024 Jul 22;14(1):16809. doi: 10.1038/s41598-024-67867-0.
5
Noncanonical Regulation of cAMP-Dependent Insulin Secretion and Its Implications in Type 2 Diabetes.非规范调节环腺苷酸依赖的胰岛素分泌及其在 2 型糖尿病中的意义。
Compr Physiol. 2023 Jun 26;13(3):5023-5049. doi: 10.1002/cphy.c220031.
6
Inhibition of microRNA-33b in humanized mice ameliorates nonalcoholic steatohepatitis.在人源化小鼠中抑制 microRNA-33b 可改善非酒精性脂肪性肝炎。
Life Sci Alliance. 2023 Jun 1;6(8). doi: 10.26508/lsa.202301902. Print 2023 Aug.
7
Adipose Tissue Secretion Pattern Influences β-Cell Wellness in the Transition from Obesity to Type 2 Diabetes.脂肪组织分泌模式影响肥胖向 2 型糖尿病转变过程中的β细胞功能。
Int J Mol Sci. 2022 May 15;23(10):5522. doi: 10.3390/ijms23105522.
8
Lipotoxicity and β-Cell Failure in Type 2 Diabetes: Oxidative Stress Linked to NADPH Oxidase and ER Stress.2 型糖尿病中的脂毒性和β细胞衰竭：与 NADPH 氧化酶和内质网应激相关的氧化应激。
Cells. 2021 Nov 26;10(12):3328. doi: 10.3390/cells10123328.
9
All-trans retinoic acid impairs glucose-stimulated insulin secretion by activating the RXR/SREBP-1c/UCP2 pathway.全反式视黄酸通过激活 RXR/SREBP-1c/UCP2 通路来损害葡萄糖刺激的胰岛素分泌。
Acta Pharmacol Sin. 2022 Jun;43(6):1441-1452. doi: 10.1038/s41401-021-00740-2. Epub 2021 Aug 20.
10
Myogenetic Oligodeoxynucleotide (myoDN) Recovers the Differentiation of Skeletal Muscle Myoblasts Deteriorated by Diabetes Mellitus.肌源性寡脱氧核苷酸（myoDN）可恢复因糖尿病而受损的骨骼肌成肌细胞的分化。
Front Physiol. 2021 May 24;12:679152. doi: 10.3389/fphys.2021.679152. eCollection 2021.
[游离脂肪酸对胰岛素分泌和作用受损的影响。β细胞脂毒性机制]
Med Sci (Paris). 2005 Dec;21 Spec No:19-25.
4
Role of the forkhead protein FoxO1 in beta cell compensation to insulin resistance.叉头蛋白FoxO1在β细胞对胰岛素抵抗的代偿中的作用。
J Clin Invest. 2006 Mar;116(3):775-82. doi: 10.1172/JCI24967. Epub 2006 Feb 16.
5
Akt induces beta-cell proliferation by regulating cyclin D1, cyclin D2, and p21 levels and cyclin-dependent kinase-4 activity.Akt通过调节细胞周期蛋白D1、细胞周期蛋白D2和p21水平以及细胞周期蛋白依赖性激酶4的活性来诱导β细胞增殖。
Diabetes. 2006 Feb;55(2):318-25. doi: 10.2337/diabetes.55.02.06.db05-0757.
6
TFE3 transcriptionally activates hepatic IRS-2, participates in insulin signaling and ameliorates diabetes.TFE3通过转录激活肝脏中的IRS-2，参与胰岛素信号传导并改善糖尿病。
Nat Med. 2006 Jan;12(1):107-13. doi: 10.1038/nm1334. Epub 2005 Dec 4.
7
Granuphilin molecularly docks insulin granules to the fusion machinery.颗粒亲和素将胰岛素颗粒在分子水平上对接至融合机制。
J Cell Biol. 2005 Oct 10;171(1):99-109. doi: 10.1083/jcb.200505179.
8
Type 2 diabetes: principles of pathogenesis and therapy.2型糖尿病：发病机制与治疗原则
Lancet. 2005;365(9467):1333-46. doi: 10.1016/S0140-6736(05)61032-X.
9
Hyperlipidemic effects of dietary saturated fats mediated through PGC-1beta coactivation of SREBP.膳食饱和脂肪通过PGC-1β对SREBP的共激活作用产生的高脂血症效应。
Cell. 2005 Jan 28;120(2):261-73. doi: 10.1016/j.cell.2004.11.043.
10
Transgenic mice overexpressing nuclear SREBP-1c in pancreatic beta-cells.在胰腺β细胞中过表达核SREBP-1c的转基因小鼠。
Diabetes. 2005 Feb;54(2):492-9. doi: 10.2337/diabetes.54.2.492.