叶黄素基于SIRT1相关信号通路调控脂代谢改善脂肪沉积

Lipid metabolism dysfunction leads to excess fatty deposits (obesity). SIRT1, NAD+-dependent histone deacetylase, has become an attractive target to prevent obesity and obesity-related diseases due to regulating lipid metabolism via mulitiple signal pathways. Previous researches show that lutein is the potential phytochemical for the prevention and treatment of obesity likely by lipid metabolism regulation and has the ability to activate SIRT1, but the detail effects and mechanisms mediated by SIRT1 pathway has not yet been elucidated. In this project, obese rats model induced by high-fat diet or transgenic method are supplemented with lutein and/or SIRT1 inhibitor. After treatments, the expresssions of SIRT1 and the SIRT1-related regulatory factors which play vital role in lipid metabolism and adipocyte differentiation such as PGC-1α、PPARα/γ、FOXO、SREBP1c are analyzed. Further, these regulatory factors’ down-stream key moleculars and enzymes involving lipogenesis (ACC, FAS, SCD1), lipid mobilization (ATGL、HSL、CPT1α、ACOX1、FAT/CD36、UCP1/3), fatty acid uptake from circulating triacylglycerols (LPL), adipocyte differentiation and browning (C/EBPα/β、PRDM16、UCP1) and mitochondriopoiesis (NRF1、TFAM), are examined in the level of mRNA, protein or enzyme activities. Finally, the ameliorative effect of lutein on fatty-deposits and the underlying mechanisms by which lutein promote lipid metabolism via multiple SIRT1-associated signaling pathways will be revealed. The results of this study will provide an effective target and new dietary strategy for the prevention and treatment of obesity and obesity-related diseases.

脂代谢失衡引起脂肪过度沉积，导致肥胖。NAD+依赖的组蛋白去乙酰化酶SIRT1可多路径调控脂代谢，已成为肥胖及肥胖相关疾病防治靶点。初步研究显示，叶黄素具有调节脂代谢防治肥胖的潜力且能激活SIRT1，但叶黄素通过SIRTI1信号途径如何调控脂代谢机制未明。本项目拟通过对高脂膳食诱导和转基因肥胖模型大鼠进行叶黄素干预，分析SIRT1变化对脂代谢和脂肪细胞分化关键调节因子PGC-1α、PPARα/γ、FOXO、SREBP1c等的影响，及对这些因子调控的脂肪酸合成关键酶（ACC、FAS、SCD1）、脂肪酸分解关键酶、脂肪酸摄取关键酶（LPL）、脂肪细胞分化及棕色化关键分子、与脂肪酸氧化有关的线粒体生成关键分子（NRF1、TFAM）等的影响，以阐明叶黄素基于SIRT1信号通路调控脂代谢改善脂肪沉积的相关机制。此项目的实施和相关成果取得可为肥胖及肥胖相关疾病防治提供积极有效的分子靶点和新的膳食策略。

防治肥胖及肥胖相关疾病已成为世界范围的首要课题。膳食中蔬菜水果所含植物化学物---叶黄素，初步研究显示能调控脂代谢，具有减肥的潜在效应。脂代谢失衡是导致肥胖的关键因素，SIRT1 是细胞能量感应分子，可在多种组织多路径调控脂肪代谢，已成为肥胖及肥胖相关疾病防治靶点。本课题通过对高脂膳食诱导的和转基因的肥胖模型大鼠进行叶黄素（LUT）干预，同时设立SIRT1激活剂（白藜芦醇，RES）和抑制剂（尼克酰胺，NAM）组，以SIRT1为靶点，研究叶黄素在机体脂代谢失衡过程中所引起的SIRT1变化，并逐步分析SIRT1变化对不同靶器官脂质代谢途径关键分子活化的影响，明确叶黄素调控脂代谢的信号通路。具体研究结果显示：（1）LUT补充显著降低了高脂喂养SD大鼠的体重及腹壁脂肪的脂质沉积，LUT+RES的联合作用显著改善了ZDF大鼠体重的增加，LUT、RES及LUT+RES组ZDF大鼠的腹壁脂肪也降低显著，而NAM补充显著增加了ZDF大鼠腹壁脂肪的蓄积。（2）LUT、RES补充显著降低了ZDF大鼠血清TG水平，且NAM补充随干预时间不同发挥了不同程度降血清TC效应。(3) 肝脏HE及油红染色均显示，SD大鼠叶黄素补充后改善了肝组织发生炎症、脂肪变性情况；ZDF大鼠LUT组肝脏脂肪变性稍有改善，RES及NAM组肝组织脂肪变性改善明显，脂滴明显减少。（4）LUT在大鼠肝脏中主要通过激活SIRT1，增加CPT1A表达及HSL蛋白磷酸化，调控肝脏脂肪酸β氧化途径，促进肝脏TG分解发挥降脂效应。（5）LUT在SD大鼠腹壁脂肪中主要通过激活SIRT1，增加ATGL蛋白表达及HSL磷酸化，促进TG分解改善脂质沉积。以上研究结果可为肥胖及肥胖相关疾病的营养防治提供积极有效的分子靶点和新的膳食策略。