硬脂酰辅酶A去饱和酶在脂代谢中的作用机理研究

Stearoly-CoA desaturase (SCD), also called delta-9 desaturase, is an ER membrane protein that plays key role in lipid biosynthesis and energy homeostasis. The expression and activity of SCD are highly associated with fat accumulation, insulin resistance, and other metabolic diseases. However, the structure and function of SCD and its regulation in lipid metabolism still remain elusive. In the last several years, we have been working on the regulation of SCD in lipid metabolism. Here, we continuously propose a series of new approaches to address the biological role of SCD in lipid metabolism. We will investigate the relationship of cytochrome b5 reductase, cytochrome b5 and SCD, determination of SCD activity by zinc or iron, characterization of SCD SNPs with its bioactivity and substrate preference, as well as the underlying mechanisms of lipid droplet regulation by SCD, and eventually the role of new SCD regulator. In conclusion, this work will further provide not only completely novel insights into the structure and activity of SCD, as well as its roles in the pathogenesis of metabolic diseases, but also new potential approaches or treatments for metabolic diseases by targeting SCD.

硬脂酰辅酶A去饱和酶（SCD），也称之为Δ9去饱和酶，是一个具四个跨膜域的调节脂肪合成和能量平衡的关键酶。SCD的表达和活性与脂肪积累、胰岛素抵抗等代谢性疾病高度相关。SCD的结构和功能、及其调控脂滴大小和脂肪储存的作用机理还有很多科学问题未知。基于我们前期一系列的研究工作基础，本项目拟开展以下研究：1）SCD活性与细胞色素b5还原酶和细胞色素b5的关系；2）锌（zinc）和铁（iron）与SCD活性和功能；3）SCD SNP位点或者氨基酸与其活性和功能；4）SCD影响脂滴大小的机理；5）影响SCD功能的新基因发掘及其作用机理研究。本项目的实施不仅扩大我们对SCD结构、功能、调控机制、及其在代谢性疾病中的作用机理的深入了解，也为SCD作为代谢性疾病的治疗靶标提供新的思路和策略。

硬脂酰辅酶A去饱和酶（SCD）是参与单不饱和脂肪酸合成的关键酶。SCD的表达和活性与脂肪积累、肥胖、脂肪肝、糖尿病等代谢性疾病高度相关。通过本项目研究，我们认真完成了以下几项工作：..1）我们发现秀丽线虫中有2个编码细胞色素b5的基因cytb-5.1和cytb-5.2，其中CYTB-5.1特异调控FAT-6/7，参与C18:1(n-9)的合成；而CYTB-5.2特异影响FAT-5，调控C16:1(n-7)的合成。此结果已在BBA-Molecular and Cell Biology of Lipids上发表。..2）我们发现SREBP响应胞内锌水平，并负调控锌代谢；锌和铁互相拮抗，调控SREBP靶基因SCD的活性和脂肪合成。这是一条新的调控SREBP-SCD功能和脂代谢的环路。该工作以封面故事发表在Journal of Lipid Research上。..3）我们通过生物信息学和功能验证试验，找出两个影响SCD底物偏好性和活性的SNP突变；以及一个决定人SCD1活性高低的SNP rs2234970。目前，我们正在进行这些SNPs调控SCD和脂质代谢与相关疾病之间的作用机制研究。..4）我们首次发现一种特异脂肪酸C17iso调控内质网的稳态，从而影响SCD的表达和功能，二者协同调控脂滴的增大，缺一不可。相关研究结果正在投稿中。..5）我们新发现了一种细胞器应激--核仁应激激活转录因子PHA-4/FoxA，上调SCD和DGAT-2等相关脂肪合成基因的表达，从而将能量转化为脂肪储存，帮助秀丽线虫抵抗饥饿。相关工作发表在Nature Communications上。..这些研究揭示了SCD及其调控因子在脂代谢中的作用机理，为研究脂代谢相关疾病提供了新的思路和潜在的治疗靶点。..在此项目资助下，已发表SCI文章8篇；另外在投SCI文章3篇。