Palmitate impairs and eicosapentaenoate restores insulin secretion through regulation of SREBP-1c in pancreatic islets.
Palmitate impairs and eicosapentaenoate restores insulin secretion through regulation of SREBP-1c in pancreatic islets.
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作者：
Kato T;Shimano H;Yamamoto T;Ishikawa M;Kumadaki S;Matsuzaka T;Nakagawa Y;Yahagi N;Nakakuki M;Hasty AH;Takeuchi Y;Kobayashi K;Takahashi A;Yatoh S;Suzuki H;Sone H;Yamada N
慢性暴露于脂肪酸会导致β细胞衰竭，通常称为脂毒性。我们研究了其机制，重点是SREBP-1c，脂肪生成的关键转录因子的贡献。研究设计和方法-我们研究了饱和和多不饱和酸对胰岛素分泌、胰岛素信号传导和β细胞功能相关基因表达的体外和体内影响。使用从C57 BL/6对照和SREBP-1缺失小鼠分离的胰岛和相关基因的腺病毒基因递送或敲低系统。C57 BL/6胰岛与棕榈酸盐孵育引起葡萄糖和钾刺激的胰岛素分泌的抑制，但添加二十碳五烯酸（EPA）恢复了这两种抑制。同时，棕榈酸激活和EPA抑制SREBP-1c的mRNA和核蛋白表达，并伴随着胰岛素受体底物2（IRS-2）和颗粒蛋白（granuphilin）等SREBP-1c靶基因的相互变化。这些棕榈酸EPA对胰岛素分泌的影响在SREBP-1无效的胰岛中被消除。IRS-2/Akt通路的抑制可能是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对其进行了补偿。解偶联蛋白-2（UCP-2）也在棕榈酸抑制胰岛素分泌中起关键作用，敲低实验证实了这一点，但SREBP-1c对UCP-2的调节是部分的。棕榈酸EPA调节胰岛素分泌的类似观察胰岛从C57 BL/6小鼠预处理饮食操作。此外，EPA给药糖尿病KK-Ay小鼠改善其胰岛中胰岛素分泌的损害。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来防止它，暗示了治疗与脂毒性相关的糖尿病的治疗潜力。
OBJECTIVE—Chronic exposure to fatty acids causes β-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 β-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.
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DOI：
10.1073/pnas.95.11.5987
发表时间：
1998-05-26
影响因子：
11.1
作者：
Horton, JD;Bashmakov, Y;Shimano, H
通讯作者：
Shimano, H
影响因子：
3.3
作者：
Coppola, T;Frantz, C;Regazzi, R
通讯作者：
Regazzi, R
影响因子：
15.9
作者：
Okamoto, H;Hribal, ML;Accili, D
通讯作者：
Accili, D
影响因子：
7.7
作者：
Matsuzaka, T;Shimano, H;Yamada, N
通讯作者：
Yamada, N
影响因子：
15.9
作者：
Bernal-Mizrachi, E;Fatrai, S;Permutt, MA
通讯作者：
Permutt, MA