XAF1 overexpression exacerbates diabetes by promoting pancreatic β-cell apoptosis.
XAF1 overexpression exacerbates diabetes by promoting pancreatic β-cell apoptosis.
复制标题
XAF1过表达通过促进胰腺β细胞凋亡而加重糖尿病。
DOI：
10.1007/s00592-022-01930-y
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发表时间：
2022-10
影响因子：
3.8
通讯作者：
Nishimura, Fusanori
中科院分区：
文献类型：
--
作者：
Nishimura, Yuki;Iwashita, Misaki;Hayashi, Masato;Shinjo, Takanori;Watanabe, Yukari;Zeze, Tatsuro;Yamashita, Akiko;Fukuda, Takao;Sanui, Terukazu;Sano, Tomomi;Asano, Tomoichiro;Nishimura, Fusanori
关键词：
胰腺β细胞凋亡可能参与了2型糖尿病的发生和发展，但其机制尚不清楚。我们先前证明巨噬细胞来源的干扰素（IFN）β诱导β细胞中的X连锁抑制因子1（XAF 1）表达，并在体外加速β细胞凋亡。在这里，我们探讨了XAF 1对β细胞功能和糖尿病进展的影响。产生胰腺β细胞选择性XAF 1过表达（Xaf 1 Tg）小鼠。Xaf 1 Tg小鼠及其野生型（WT）同窝仔喂食正常饮食或40%或60%高脂饮食（HFD）。研究β细胞XAF 1对β细胞凋亡和糖尿病加重的影响。棕榈酸诱导巨噬细胞中IFNβ的表达，HFD摄入促进胰岛中巨噬细胞的浸润，两者协同上调小鼠胰岛中XAF 1的表达。此外，与喂食相同饮食的WT小鼠相比，喂食HFD的Xaf 1 Tg小鼠表现出β细胞凋亡增加、胰岛素表达降低和葡萄糖耐量受损。这些影响在60%HFD组中比在40%HFD组中更明显。HFD诱导的巨噬细胞来源的IFNβ可增强胰腺β细胞XAF 1的表达，从而促进β细胞凋亡并导致胰岛素分泌减少和糖尿病进展。据我们所知，这是第一份证明胰腺β细胞XAF 1过表达与糖尿病恶化之间相关的报告，从而为糖尿病中β细胞质量减少的机制提供了见解。在线版本包含补充材料，可通过10.1007/s 00592 -022-01930-y获得。
Pancreatic β-cell apoptosis may be involved in the onset and progression of type 2 diabetes mellitus, although its mechanism remains unclear. We previously demonstrated that macrophage-derived interferon (IFN) β induced X-linked inhibitor of apoptosis–associated factor 1 (XAF1) expression in β-cells and accelerated β-cell apoptosis in vitro. Here, we explored the effects of XAF1 on β-cell function and progression of diabetes in vivo. Pancreatic β-cell-selective XAF1 overexpressing (Xaf1 Tg) mice were generated. Xaf1 Tg mice and their wild-type (WT) littermates were fed either a normal diet or a 40% or 60% high-fat diet (HFD). The effects of β-cell XAF1 on β-cell apoptosis and exacerbation of diabetes were investigated. Palmitic acid induced IFNβ expression in macrophages, and HFD intake promoted macrophage infiltration in pancreatic islets, both of which cooperatively upregulated XAF1 expression in mouse islets. Furthermore, HFD-fed Xaf1 Tg mice demonstrated increased β-cell apoptosis, lowered insulin expression, and impaired glucose tolerance compared with WT mice fed the same diet. These effects were more pronounced in the 60%HFD group than in the 40%HFD group. Pancreatic β-cell XAF1 expression was enhanced via HFD-induced, macrophage-derived IFNβ, which promoted β-cell apoptosis and led to a reduction in insulin secretion and progression of diabetes. To our knowledge, this is the first report to demonstrate an association between pancreatic β-cell XAF1 overexpression and exacerbation of diabetes, thus providing insight into the mechanism of β-cell mass reduction in diabetes. The online version contains supplementary material available at 10.1007/s00592-022-01930-y.
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