Enhancing Acsl4 in absence of mTORC2/Rictor drove β-cell dedifferentiation via inhibiting FoxO1 and promoting ROS production
Enhancing Acsl4 in absence of mTORC2/Rictor drove β-cell dedifferentiation via inhibiting FoxO1 and promoting ROS production
复制标题
在 mTORC2/Rictor 缺失的情况下增强 Acsl4 通过抑制 FoxO1 和促进 ROS 产生来驱动 β 细胞去分化
DOI：
10.1016/j.bbadis.2021.166261
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发表时间：
2021-09-17
影响因子：
6.2
通讯作者：
Gu, Yanyun
中科院分区：
文献类型：
--
作者：
Cui, Canqi;Li, Tingting;Gu, Yanyun
Rapamycin mechanistic target of Rapamycin （Rictor）的不敏感伴侣，mTOR复合物2 （mTORC2）的关键成分，控制β细胞的增殖和功能。我们试图研究长链酰基辅酶a合成酶4 （Acs14）是否在Rictor/mTORC2下游发挥作用，以维持β细胞的功能质量。我们发现Acs14在小鼠β细胞的转录和翻译后水平受到Rictor的正调控。在β细胞特异性敲除Rictor（β RicKO）的胰岛中感染表达Acs14的腺病毒和用慢病毒表达sirna寡核苷酸靶向Rictor（siRic）敲除Rictor的Min6细胞，可恢复β细胞发育不良，但未恢复功能障碍。海马XF细胞生物能量实验表明，Acs14不能恢复rictor缺失β细胞中被抑制的葡萄糖氧化，但能进一步促进脂质氧化。转座酶可及染色质（ATAC）和H3K27Ac染色质免疫沉淀（ChIP）测序研究反映了β细胞去分化和减轻氧化防御/反应的表观遗传升高的分子特征。在Acs14过表达rictor -缺乏β细胞中，fox01乙酰化和泛素化升高，Gpxl和Hiflan蛋白水平升高，活性氧（ROS）产生过多，MafA减少，这些结果得到了证实。在这些细胞中，抗氧化处理显著恢复了MafA水平和胰岛素含量。单独诱导脂质氧化不能模拟Acs14对Rictor缺乏β细胞的作用。我们的研究表明，Acs14在β细胞中的功能是上下文依赖的，并且可能通过翻译后抑制fox01和表观遗传增强ROS诱导的MafA降解，通过减弱Rictor/mTORC2活性或胰岛素信号传导来促进β细胞去分化。
Rapamycin insensitive companion of mechanistic target of Rapamycin (Rictor), the key component of mTOR complex 2 (mTORC2), controls both beta-cell proliferation and function. We sought to study whether long chain acyl-CoA synthetase 4 (Acs14) worked downstream of Rictor/mTORC2 to maintain beta-cell functional mass. We found Acs14 was positively regulated by Rictor at transcriptional and posttranslational levels in mouse beta-cell. Infecting adenovirus expressing Acs14 in beta-cell-specific-Rictor-knockout (beta RicKO) islets and Min6 cells knocking down Rictor with lentivirus-expressing siRNA-oligos targeting Rictor(siRic), recovered the beta-cell dysplasia but not dysfunction. Cell bioenergetic experiment performed with Seahorse XF showed that Acs14 could not rescue the dampened glucose oxidation in Rictor-lacking beta-cell, but further promoted lipid oxidation. TransposaseAccessible Chromatin (ATAC) and H3K27Ac chromatin immunoprecipitation (ChIP) sequencing studies reflected the epigenetic elevated molecular signature for beta-cell dedifferentiation and mitigated oxidative defense/response. These results were confirmed by the observations of elevated acetylation and ubiquitination of FoxO1, increased protein levels of Gpxl and Hiflan, excessive reactive oxygen species (ROS) production and diminished MafA in Acs14 overexpressed Rictor-lacking beta-cells. In these cells, antioxidant treatment significantly recovered MafA level and insulin content. Inducing lipid oxidation alone could not mimic the effect of Acs14 in Rictor lacking beta-cell. Our study suggested that Acs14 function in (beta-cell was context dependent and might facilitate beta-cell dedifferentiation with attenuated Rictor/mTORC2 activity or insulin signaling via posttranslational inhibiting FoxO1 and epigenetically enhancing ROS induced MafA degradation.