CIDEA Transcriptionally Regulates UCP1 for Britening and Thermogenesis in Human Fat Cells
CIDEA Transcriptionally Regulates UCP1 for Britening and Thermogenesis in Human Fat Cells
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DOI：
10.1016/j.isci.2019.09.011
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发表时间：
2019-10-25
期刊：
影响因子：
5.8
通讯作者：
Puri, Vishwajeet
中科院分区：
文献类型：
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作者：
Jash, Sukanta;Banerjee, Sayani;Puri, Vishwajeet
我们的研究确定了细胞死亡诱导DNA片段化因子样效应子A（CIDEA）的转录作用，CIDEA是一种脂滴相关蛋白，它调节人类脂肪细胞变亮/变白，从而调节能量消耗。全面的转录组分析揭示了CIDEA对brite/beige人脂肪细胞中产热功能的控制。在不存在CIDEA的情况下，通过修饰的基于双RNA的CRISPR-Cas9 n（D10 A）系统实现，脂肪细胞失去了它们的增亮能力，这在CIDEA再表达时恢复。解偶联蛋白1（UCP 1）是人脂肪细胞中上调最多的基因，在CIDEA敲除（KO）原代人脂肪细胞中受到抑制。从机制上讲，在诱导变亮期间，CIDEA以浓度依赖性方式通过不寻常的核二分信号从脂滴穿梭到细胞核。在细胞核中，它特异性地抑制LXR α对UCP 1增强子活性的抑制，并增强PPAR γ与UCP 1增强子的结合，从而驱动UCP 1转录。总的来说，我们的研究确定了CIDEA在增加人脂肪细胞产热中的作用。
Our study identifies a transcriptional role of cell death-inducing DNA fragmentation factor-like effector A (CIDEA), a lipid-droplet-associated protein, whereby it regulates human adipocyte britening/beiging with consequences for the regulation of energy expenditure. The comprehensive transcriptome analysis revealed CIDEA's control over thermogenic function in brite/beige human adipocytes. In the absence of CIDEA, achieved by the modified dual-RNA-based CRISPR-Cas9n(D10A) system, adipocytes lost their britening capability, which was recovered upon CIDEA re-expression. Uncoupling protein 1 (UCP1), the most upregulated gene in brite human adipocytes, was suppressed in CIDEA knockout (KO) primary human adipocytes. Mechanistically, during induced britening, CIDEA shuttled from lipid droplets to the nucleus via an unusual nuclear bipartite signal in a concentration-dependent manner. In the nucleus, it specifically inhibited LXRa repression of UCP1 enhancer activity and strengthened PPAR gamma binding to UCP1 enhancer, hence driving UCP1 transcription. Overall, our study defines the role of CIDEA in increasing thermogenesis in human adipocytes.