首页> 美国卫生研究院文献>The Journal of Clinical Investigation >HDAC6-mediated acetylation of lipid droplet–binding protein CIDEC regulates fat-induced lipid storage
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HDAC6-mediated acetylation of lipid droplet–binding protein CIDEC regulates fat-induced lipid storage

机译:HDAC6介导的脂质液滴结合蛋白CIDEC的乙酰化调节脂肪诱导的脂质存储

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摘要

Obesity is characterized by aberrant fat accumulation. However, the intracellular signaling pathway that senses dietary fat and leads to fat storage remains elusive. Here, we have observed that the levels of histone deacetylase 6 (HDAC6) and the related family member HDAC10 are markedly reduced in adipose tissues of obese animals and humans. Mice with adipocyte-specific depletion of Hdac6 exhibited increased fat accumulation and reduced insulin sensitivity. In normal adipocytes, we found that reversal of P300/CBP-associated factor–induced (PCAF-induced) acetylation at K56 on cell death-inducing DFFA-like effector C (CIDEC, also known as FSP27) critically regulated lipid droplet fusion and lipid storage. Importantly, HDAC6 deacetylates CIDEC, leading to destabilization and reduced lipid droplet fusion. Accordingly, we observed elevated levels of CIDEC and its acetylated form in HDAC-deficient adipocytes as well as the adipose tissue of obese animals and humans. Fatty acids (FAs) prevented CIDEC deacetylation by promoting the dissociation of CIDEC from HDAC6, which resulted in increased association of CIDEC with PCAF on the endoplasmic reticulum. Control of CIDEC acetylation required the conversion of FAs to triacylglycerols. Thus, we have revealed a signaling axis that is involved in the coordination of nutrient availability, protein acetylation, and cellular lipid metabolic responses.
机译:肥胖症的特征是脂肪堆积异常。然而,感觉饮食脂肪并导致脂肪储存的细胞内信号传导途径仍然难以捉摸。在这里,我们已经观察到,肥胖动物和人的脂肪组织中组蛋白脱乙酰基酶6(HDAC6)和相关家族成员HDAC10的水平明显降低。 Hdac6的脂肪细胞特异性消耗的小鼠表现出增加的脂肪积累和降低的胰岛素敏感性。在正常脂肪细胞中,我们发现在细胞死亡诱导的DFFA样效应子C(CIDEC,也称为FSP27)上,K56上P300 / CBP相关因子诱导的(PCAF诱导的)乙酰化的逆转关键地调节了脂质滴的融合和脂质存储。重要的是,HDAC6使CIDEC脱乙酰,导致不稳定并减少脂质滴融合。因此,我们观察到肥胖动物和人类的HDAC缺乏脂肪细胞以及脂肪组织中CIDEC及其乙酰化形式的水平升高。脂肪酸(FAs)通过促进CIDEC从HDAC6的解离来阻止CIDEC脱乙酰基作用,从而导致CIDEC与PCAF在内质网上的缔合增加。控制CIDEC乙酰化需要将FAs转化为三酰基甘油。因此,我们揭示了一个信号轴,该轴参与营养物的利用,蛋白质乙酰化和细胞脂质代谢反应的协调。

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