Tip60在脂代谢调控中的作用机制研究

The intracellular storage and utilization of lipids are critical to maintain cellular energy homeostasis of humans and many other organisms. Dysfunction of lipid metabolism is also associated with diverse metabolic disorders including obesity and diabetes. Although pathways that mediate the synthesis or breakdown of lipids have been generally elucidated, how these pathways are precisely regulated was largely unknown. We previously found that Tip60S86A knock-in mice exhibit marked reduction in the percentage of fat mass compared to that in wild type mice; knockdown of Tip60 leads to severely reduced rate of lipid accumulation in response to oleic acid stimulation. Based on our current preliminary data, we aim to investigate the role of Tip60 in the modulation of lipid metabolic pathways and the mechanisms underlying the phenotypes of Tip60S86A knock-in mice pertaining to dysregulated fat storage. The proposed work will make a major contribution to the understanding of the molecular mechanisms for the regulation of lipid metabolism as well as the pathogenesis of obesity and diabetes, ultimately providing new therapeutic avenues for the prevention and treatment of these metabolic disorders.

脂肪的正常储存与合理利用是机体维持能量与物质代谢稳态的关键因素。脂代谢的紊乱也是引起肥胖、糖尿病等一系列代谢紊乱病的重要原因。尽管脂代谢的合成与分解通路已经被基本解析，其具体调控机理的阐述还处于初步阶段。我们的前期研究发现，Tip60S86A基因敲入小鼠体内的脂肪含量与野生型小鼠相比出现了显著的降低，Tip60稳定低表达的细胞在外源脂肪酸处理时细胞内脂肪的积累能力受到了大幅削弱，这些证据提示我们Tip60在脂肪积累过程中可能发挥着十分重要的作用。我们拟应用分子生物学、生化重组和细胞生物学方法，结合小鼠模型和细胞实验，研究Tip60调控脂代谢的分子机制，加深我们对脂代谢调控方式的认识，为我们进一步理解肥胖和糖尿病的发生机理做出贡献。

肥胖的特征之一是脂肪组织中过量的脂肪酸通过脂肪合成途径转化成甘油三酯。然而，目前对机体如何感知脂肪酸以及脂肪酸如何促进脂类合成的机制还知之甚少。本研究构建了乙酰转移酶Tip60第86位磷酸化位点突变的基因敲入小鼠（Tip60SA/SA），并发现该突变小鼠与野生型小鼠相比其机体脂肪含量急剧减少（下降60 %左右）。而且，该突变小鼠能显著抵御高脂诱导的肥胖，同时改善高脂诱发的代谢紊乱包括缓解脂肪肝和改善胰岛素抵抗。同时，该研究发现，由于乳汁中脂肪含量急剧降低，导致Tip60SA/SA母鼠无法正常哺育幼崽。机制上，在脂肪酸或高脂刺激下，Tip60能直接乙酰化磷脂酸磷酸酶lipin 1，而lipin 1具有催化磷脂酸去磷酸化合成甘油二酯，进而参与甘油三酯合成的功能。接着，乙酰化修饰后的lipin 1，从细胞溶质转运到内质网相关的膜（内质网是脂肪合成的场所）上，从而促进脂肪的合成。本研究还进一步揭示了去乙酰化酶SIRT1能够去乙酰化lipin 1，进而抑制lipin 1的内质网转运，从而抑制脂肪的合成。因此，本研究发现了一条Tip60参与并介导lipin1乙酰化修饰调控脂肪合成的作用机制，这或许能为治疗肥胖提供新的思路。