State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian, 361102, China.
School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
Nat Commun. 2018 May 15;9(1):1916. doi: 10.1038/s41467-018-04363-w.
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 phosphorylation site of acetyltransferase Tip60 (Tip60 ) display remarkably reduced body fat mass, and Tip60 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.
肥胖的特征是脂肪组织中脂肪酸过多地转化为三酰基甘油（TAGs）。然而，信号网络如何感知脂肪酸并与脂质合成的刺激相联系仍然难以捉摸。在这里，我们展示了携带乙酰转移酶 Tip60（Tip60）丝氨酸磷酸化位点点突变的纯合敲入小鼠表现出明显减少的体脂肪量，并且 Tip60 雌性由于乳 TAGs 严重减少而无法将幼崽养育至成年。在机制上，脂肪酸刺激 Tip60 依赖性乙酰化和磷酸酶 lipin 1 的内质网易位，以生成用于 TAG 合成的二酰基甘油，该反应被去乙酰化酶 Sirt1 抑制。Tip60 活性的抑制强烈阻止脂肪酸诱导的 TAG 合成，而 Sirt1 的抑制导致脂肪增多。酿酒酵母中丧失功能突变体的遗传分析揭示了 Tip60 的酵母同源物 ESA1 在 TAG 积累中的必需性。这些发现揭示了将脂肪酸感应与脂肪合成联系起来的保守机制。
