Role of Stearoyl-CoA Desaturase in Metabolism

描述（由申请人提供）：本提案的目的是揭示硬脂酰辅酶A去饱和酶（SCD）表达在储存和氧化之间分配脂质的分子机制。了解脂质体内平衡的基础是开发新策略以对抗肥胖、糖尿病和其他脂质代谢异常疾病的基础。SCD是催化单不饱和脂肪酸（主要是油酸酯（C18：1），甘油三酯、胆固醇酯、蜡酯和磷脂的主要单不饱和脂肪酸）合成的中心酶。在先前的资助申请中的研究表明，具有SCD 1亚型（SCD 1-/-）的靶向破坏的小鼠具有减少的脂肪生成基因表达，增加的脂肪酸氧化和增强的胰岛素敏感性。SCD 1-/-小鼠比对照小鼠更瘦，对饮食和瘦素缺乏诱导的肥胖具有抗性，并且具有减少的肝脏脂肪变性。SCD 1缺乏引起上述表型的机制仍然知之甚少。我们最近观察到，尽管在用高碳水化合物无脂饮食喂养SCD 1-/-小鼠后血浆胰岛素增加，但过氧化物酶体增殖物激活受体γ共激活剂（PGC-1a）的基因表达（包括脂肪酸B-氧化和促凋亡基因）在进食状态下增加。此外，成熟固醇调节元件结合蛋白-1（SREBP-1）的表达不增加，并且SREBP-1c靶基因的表达不被诱导。有趣的是，insig-2a的基因表达和蛋白质水平增加，insig-2a是一种通过将SREBP保留在ER中来阻断SREBP成熟的蛋白质，通常被胰岛素抑制。人SCD在小鼠肝脏中的转基因过表达增加了成熟SREBP-1蛋白和脂肪生成基因的表达。我们推测，细胞18：1/18：0的比例调节肝脏脂质代谢在餐后状态下，通过调节PGC-1a和insig-2a蛋白的表达。我们将设计实验，以解决这一假设，在体内和体外的方法。这项建议的两个具体目标是：1.检测肝脏SCD 1缺乏是否通过调节PGC-1a的表达增加餐后状态下线粒体脂肪酸B氧化。2.检测肝脏SCD 1缺乏是否通过增加insig-2a表达阻断SREBP-1加工并下调餐后状态下的脂肪生成。餐后脂肪蓄积是饮食诱导肥胖和2型糖尿病的主要原因之一。我们已经发现了一种机制，将脂肪从储存中分离出来，并在进食状态下燃烧。我们的研究将有助于人类肥胖、糖尿病和其他代谢性疾病的治疗。

DESCRIPTION (provided by applicant): The objective of this proposal is to reveal molecular mechanisms by which stearoyl-CoA desaturase (SCD) expression partitions lipids between storage and oxidation. Understanding the basis of lipid homeostasis is fundamental to developing new strategies to combat obesity, diabetes and other diseases of abnormal lipid metabolism. SCD is a central enzyme catalyzing the synthesis of monounsaturated fatty acids, mainly oleate (C18:1), the major monounsaturated fatty acid of triglycerides, cholesterol esters, wax esters and phospholipids. Studies in the previous grant application demonstrated that mice with a targeted disruption of SCD1 isoform (SCD1-/-) have reduced lipogenic gene expression, increased fatty acid oxidation and enhanced insulin sensitivity. The SCD1-/- mice are leaner than control mice, resistant to both diet- and leptin deficiency-induced obesity and have reduced liver steatosis. The mechanisms by which SCD1 deficiency elicits the aforementioned phenotypes are still poorly understood. We have recently observed that despite an increase in plasma insulin upon feeding SCD1-/- mice with a high carbohydrate fat-free diet, the gene expression of peroxisome proliferator-activated receptor y co-activator (PGC-1a) including the fatty acid B-oxidation and gluconeogenic genes is increased in the fed state. Furthermore, the expression of the mature sterol regulatory element binding protein-1 (SREBP-1) is not increased and that of the SREBP-1c target genes is not induced. Interestingly, the gene expression and protein levels of insig-2a, a protein that blocks maturation of SREBPs by retaining them in the ER and is normally repressed by insulin is increased. Transgenic over expression of human SCD in mouse liver increases the expression of the mature SREBP-1 protein and that of lipogenic genes. We hypothesize that the cellular 18:1/18:0 ratio regulates hepatic lipid metabolism in the postprandial state by modulating the expression of PGC-1a and insig-2a proteins. We will design experiments to address this hypothesis using in vivo and in vitro approaches. The two specific aims of this proposal are: 1. To test whether hepatic SCD1 deficiency increases mitochondrial fatty acid B-oxidation in the postprandial state by regulating the expression of PGC-1a. 2. To test whether hepatic SCD1 deficiency blocks SREBP-1 processing and down regulates lipogenesis in the postprandial state by increasing insig-2a expression. Fat storage after a meal is one of the major causes of diet induced-obesity and type 2 diabetes. We have discovered a mechanism that partitions fat away from storage towards its burning in the fed state. Our research will contribute to the treatment of human obesity, diabetes and other metabolic diseases.