Plin2-mediated lipid droplet mobilization accelerates exit from pluripotency by lipidomic remodeling and histone acetylation
Plin2-mediated lipid droplet mobilization accelerates exit from pluripotency by lipidomic remodeling and histone acetylation
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Plin2介导的脂滴动员通过脂质组学重塑和组蛋白乙酰化加速多能性的退出
DOI：
10.1038/s41418-022-01018-8
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发表时间：
2022-05
影响因子：
12.4
通讯作者：
Liu Xingguo
中科院分区：
文献类型：
--
作者：
Wu Yi;Chen Keshi;Li Linpeng;Hao Zhihong;Wang Tianyu;Liu Yang;Xing Guangsuo;Liu Zichao;Li Heying;Yuan Hao;Lu Jianghuan;Zhang Cheng;Zhang Jinye;Zhao Danyun;Wang Junwei;Nie Jinfu;Ye Dan;Pan Guangjin;Chan Wai-Yee;Liu Xingguo
代谢开关对于通过代谢功能、表观遗传修饰和基因表达决定细胞命运至关重要。然而，这些改变背后的机制及其功能作用仍不清楚。在这里，我们证明 Plin2 介导的适度脂质水解对于胚胎干细胞 (ESC) 的多能性至关重要。退出多能性后，脂滴 (LD) 相关蛋白 Plin2 被 Hsc70 识别，并通过分子伴侣介导的自噬降解，以促进 LD 动员。通过 Plin2 敲除增强脂质水解可促进多能性退出，通过 ATGL 抑制可恢复多能性。从机制上讲，过度的脂质水解会引起显着的脂质组学重塑，其特征是心磷脂和磷脂酰乙醇胺减少，从而引发线粒体嵴和脂肪酸氧化缺陷，导致乙酰辅酶A和组蛋白乙酰化减少。我们的研究结果揭示了 LD 动员的调节方式及其在 ESC 多能性中的关键作用，并表明了 LD 稳态与线粒体重塑和表观遗传调控之间的联系机制，这可能为发育和疾病提供线索。
Metabolic switch is critical for cell fate determination through metabolic functions, epigenetic modifications, and gene expression. However, the mechanisms underlying these alterations and their functional roles remain unclear. Here, we show that Plin2-mediated moderate lipid hydrolysis is critical for pluripotency of embryonic stem cells (ESCs). Upon exit from pluripotency, lipid droplet (LD)-associated protein Plin2 is recognized by Hsc70 and degraded via chaperone-mediated autophagy to facilitate LD mobilization. Enhancing lipid hydrolysis by Plin2 knockout promotes pluripotency exit, which is recovered by ATGL inhibition. Mechanistically, excessive lipid hydrolysis induces a dramatic lipidomic remodeling characterized by decreased cardiolipin and phosphatidylethanolamine, which triggers defects in mitochondrial cristae and fatty acid oxidation, resulting in reduced acetyl-CoA and histone acetylation. Our results reveal how LD mobilization is regulated and its critical role in ESC pluripotency, and indicate the mechanism linking LD homeostasis to mitochondrial remodeling and epigenetic regulation, which might shed light on development and diseases.
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影响因子：
5.2
作者：
He R;Dantas A;Riabowol K
通讯作者：
Riabowol K
影响因子：
46.9
作者：
Guijas C;Montenegro-Burke JR;Warth B;Spilker ME;Siuzdak G
通讯作者：
Siuzdak G
影响因子：
29
作者：
Liu L;MacKenzie KR;Putluri N;Maletić-Savatić M;Bellen HJ
通讯作者：
Bellen HJ
影响因子：
29
作者：
TeSlaa T;Chaikovsky AC;Lipchina I;Escobar SL;Hochedlinger K;Huang J;Graeber TG;Braas D;Teitell MA
通讯作者：
Teitell MA
影响因子：
10.9
作者：
Stein, Liana Roberts;Imai, Shin-ichiro
通讯作者：
Imai, Shin-ichiro