铁和铁蛋白对脂肪储存的影响及其分子机理研究

Iron is an essential element for nearly all living species because it is an important oxygen and eletron carrier. The levels of iron and ferritin, which is an ubiquitous intracellular protein that stores iron, are tightly associated with obesity, diabetes, non-alcoholic fatty liver disease (NAFLD), and other metabolic syndromes. However, the precise mechanisms of how iron and ferritin regulate lipid metabolism are unclear. Like mammals, the genome of model organism Caenorhabditis elegans contains most of genes involved in iron homeostasis. Furthermore, the biological functions of these iron-related genes in C.elegans are conserved and also are reugalted by iron. We currently found that iron indeed regulates lipid metabolism, and genes involved in iron homeostasis affect fat storage in C.elegans. Therefore, we propose several approaches to understand the precise mechanisms of iron and ferritin in the regulation of lipid metabolism. To do so, firstly, we will confirm how many and which genes involved in iron homeostasis actually affect lipid metabolism, as well as their relationship through genetic and biochemical approaches. And secondly, we will search for genes whose expression is regulated by iron via transcriptome and how it response to iron in the regulation of fat storage. In the end, we will search for the regulators of ferritin by whole-genome RNAi screen, and further figure out how these regulators of ferritin works with/on ferritin to regulate lipid metabolism. In conclusion, this work will eveutally provide new insights into the mechanisms of iron and ferritin in the regulation of lipid metabolism, as well as probably present new regulators of iron homeostasis and lipid metabolism, which may be potentail targets for therapy of iron-related metabolic syndromes.

铁是重要的氧载体和电子传递体，是生物体必需的微量元素。机体中铁和铁蛋白（ferritin）的水平与肥胖、糖尿病、非酒精性脂肪肝等代谢性疾病密切相关。然而，铁和铁蛋白对脂代谢的影响及其机理并不是很清楚。模式生物秀丽线虫是研究脂代谢调控的良好模型，并且其基因组中具有与哺乳动物类似的绝大部分参与铁代谢的基因。我们目前的研究发现：铁影响秀丽线虫脂肪储存，铁代谢相关基因参与脂代谢。在此基础上，我们提出：1.利用遗传和生化方法，明确铁、铁代谢相关基因和脂肪储存的关系；2.比较转录组学寻找受铁调控的基因，进而研究其响应铁而影响脂肪储存的机制；3.利用秀丽线虫大规模遗传筛选的优势，基因组筛选调控铁蛋白（FTN-1）的基因，研究它们和铁蛋白影响脂肪储存的分子机制。本项目将加深我们对铁和铁蛋白影响脂代谢的分子机理的了解；同时很可能发掘到新的调控铁和脂代谢的基因，为治疗和铁相关的代谢性疾病提供新靶点和途径。

铁过载导致脂肪积累，其作用机理不清楚。我们利用模式生物秀丽线虫，发现血清与糖皮质激素诱导激酶SGK-1在铁过载引起的脂肪积累中扮演重要角色。铁过载上调SGK-1表达，SGK-1进而调控铁蛋白FTN-1的表达，以及脂类转运蛋白ACS-20和VIT-2的表达，促进脂类的吸收和储存。细胞色素P450家族成员CYP-23A1很可能作用与SGK-1的上游，对SGK-1在促进脂类吸收和铁吸收的功能起到抑制作用。另外，硬脂酰辅酶A去饱和酶SCD 是参与脂肪合成的一个关键酶。我们发现，铁和锌离子拮抗决定SCD的活性，当SCDs结合锌离子时没有催化活性。相反，当锌离子缺乏时，铁与SCDs的结合作用增强，促进脂肪合成和积累。电子从细胞色素B5还原酶传递给细胞色素B5，再交给SCD的Fe原子，激活SCD。秀丽线虫拥有3个SCD，分别为FAT-5、FAT-6和FAT-7，催化不同底物反应。我们发现，CYTB-5.1特异性的调控FAT-6和FAT-7的活性，而CYTB-5.2特异性的调控FAT-5的活性。研究工作揭示了锌和铁互相拮抗，调控SREBP及靶基因SCD的功能和脂肪合成这样一条新的调控SREBP-SCD功能和脂代谢的环路，为研究铁及锌代谢与脂代谢及其相关代谢性疾病提供了新的思路和潜在的治疗靶点.