A role and mechanism for redox sensing by SENP1 in β-cell responses to high fat feeding.
A role and mechanism for redox sensing by SENP1 in β-cell responses to high fat feeding.
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DOI：
10.1038/s41467-023-44589-x
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发表时间：
2024-01-06
影响因子：
16.6
通讯作者：
MacDonald, Patrick E.
中科院分区：
文献类型：
--
作者：
Lin, Haopeng;Suzuki, Kunimasa;Smith, Nancy;Li, Xi;Nalbach, Lisa;Fuentes, Sonia;Spigelman, Aliya F.;Dai, Xiao-Qing;Bautista, Austin;Ferdaoussi, Mourad;Aggarwal, Saloni;Pepper, Andrew R.;Roma, Leticia P.;Ampofo, Emmanuel;Li, Wen-hong;MacDonald, Patrick E.
胰腺β细胞通过上调胰岛素分泌来响应代谢应激，然而其潜在机制仍不清楚。在这里，我们发现，在来自无糖尿病的超重人类和高脂饮食喂养2天的小鼠的β细胞中，胰岛素胞吐和分泌增强，而没有增加Ca2+内流。分选的β-细胞的RNA-seq表明在高脂肪饮食后早期改变的代谢途径，其中我们发现增加的基础氧消耗和质子泄漏，但更减少的胞质氧化还原状态。2天高脂饮食后增加的β细胞胞吐作用依赖于这种降低的细胞内氧化还原状态，并且需要sentrin特异性SUMO蛋白酶-1。具有胰腺或β细胞特异性缺失的小鼠不能上调胞吐作用，并且在2天高脂肪饮食后迅速变得葡萄糖不耐受。从机制上讲，SUMO蛋白酶的氧化还原感测需要C535处的巯基，其与Zn+结合一起抑制基础蛋白酶活性和不受限制的β细胞胞吐作用，并增加酶对氧化还原信号调节的敏感性。胰岛素分泌适应代谢需要，但这在短期内如何发生尚不清楚。在这里，作者表明这涉及β细胞胞吐作用的上调，并且需要SUMO蛋白酶SENP 1，其以锌依赖性方式响应氧化还原状态。
Pancreatic β-cells respond to metabolic stress by upregulating insulin secretion, however the underlying mechanisms remain unclear. Here we show, in β-cells from overweight humans without diabetes and mice fed a high-fat diet for 2 days, insulin exocytosis and secretion are enhanced without increased Ca2+ influx. RNA-seq of sorted β-cells suggests altered metabolic pathways early following high fat diet, where we find increased basal oxygen consumption and proton leak, but a more reduced cytosolic redox state. Increased β-cell exocytosis after 2-day high fat diet is dependent on this reduced intracellular redox state and requires the sentrin-specific SUMO-protease-1. Mice with either pancreas- or β-cell-specific deletion of this fail to up-regulate exocytosis and become rapidly glucose intolerant after 2-day high fat diet. Mechanistically, redox-sensing by the SUMO-protease requires a thiol group at C535 which together with Zn+-binding suppresses basal protease activity and unrestrained β-cell exocytosis, and increases enzyme sensitivity to regulation by redox signals. Insulin secretion adapts to metabolic needs, but how this happens over the short term is not clear. Here the authors show this involves upregulation of beta-cell exocytosis and requires the SUMO-protease SENP1, which responds to redox state in a zinc-dependent manner.
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影响因子：
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