Tip60-mediated lipin 1 acetylation and ER translocation determine triacylglycerol synthesis rate
Tip60-mediated lipin 1 acetylation and ER translocation determine triacylglycerol synthesis rate
复制标题
Tip60介导的脂质1乙酰化和ER易位决定三酰甘油合成率
DOI：
10.1038/s41467-018-04363
复制
发表时间：
2018-05-15
影响因子：
16.6
通讯作者：
Lin, Sheng-Cai
中科院分区：
文献类型：
--
作者：
Li, Terytty Yang;Song, Lintao;Lin, Sheng-Cai
肥胖的特征在于脂肪组织中脂肪酸过度转化为三酰基甘油（TAG）。然而，信号网络如何感知脂肪酸并连接到脂质合成的刺激仍然是难以捉摸的。在这里，我们表明，在乙酰转移酶Tip 60（Tip 60（SA/SA））的Ser（86）磷酸化位点携带点突变的纯合基因敲入小鼠显示出显着减少的体脂量，和Tip 60（SA/SA）的女性未能培育幼崽成年由于严重减少牛奶TAG。从机制上讲，脂肪酸刺激磷脂酸磷酸酶lipin 1的Tip 60依赖性乙酰化和内质网移位，产生用于TAG合成的二酰基甘油，而TAG合成被脱乙酰酶Sirt 1抑制。Tip 60活性的抑制强烈阻断脂肪酸诱导的TAG合成，而Sirt 1抑制导致肥胖增加。酿酒酵母中功能丧失突变体的遗传分析揭示了Tip 60的酵母直系同源物ESA 1在TAG积累中的需求。这些发现揭示了脂肪酸传感与脂肪合成之间的保守机制。
Obesity is characterized by excessive fatty acid conversion to triacylglycerols (TAGs) in adipose tissues. However, how signaling networks sense fatty acids and connect to the stimulation of lipid synthesis remains elusive. Here, we show that homozygous knock-in mice carrying a point mutation at the Ser(86) phosphorylation site of acetyltransferase Tip60 (Tip60(SA/SA)) display remarkably reduced body fat mass, and Tip60(SA/SA) females fail to nurture pups to adulthood due to severely reduced milk TAGs. Mechanistically, fatty acids stimulate Tip60-dependent acetylation and endoplasmic reticulum translocation of phosphatidic acid phosphatase lipin 1 to generate diacylglycerol for TAG synthesis, which is repressed by deacetylase Sirt1. Inhibition of Tip60 activity strongly blocks fatty acid-induced TAG synthesis while Sirt1 suppression leads to increased adiposity. Genetic analysis of loss-of-function mutants in Saccharomyces cerevisiae reveals a requirement of ESA1, yeast ortholog of Tip60, in TAG accumulation. These findings uncover a conserved mechanism linking fatty acid sensing to fat synthesis.