Role of Stearoyl-CoA Desaturase in Metabolism

描述（由申请人提供）：硬脂酰-CoA去饱和酶是一种中心脂肪生成酶，催化单不饱和脂肪酸（主要是油酸酯（C18：1）和棕榈油酸酯（C16：1））合成中的所有反应，这些单不饱和脂肪酸是膜磷脂、甘油三酯、蜡酯和胆固醇酯的主要单不饱和脂肪酸。在小鼠中存在几种SCD基因亚型（SCD 1、SCD 2、SCD 3）。我们已经发现，具有SCD 1同种型（SCD 1-/-）的靶向破坏的小鼠具有降低的体脂、血浆瘦素和胰岛素水平以及降低的肝脏中甘油三酯合成速率。与野生型小鼠相比，SCD 1-/-小鼠是瘦的并且抵抗高脂肪饮食诱导的肥胖。在SCD 1-/-小鼠中，脂肪生成基因的表达减少。众所周知，脂肪酸和甘油三酯的合成受胰岛素依赖性基因表达和固醇调节元件结合蛋白-ic（SREBP-1c）成熟的调节。相反，我们发现，虽然SREBP-1c基因表达在SCD 1-/-小鼠中没有改变，但SREBP-1蛋白成熟为转录活性形式被阻断。酮体水平和过氧化物酶体增殖物激活受体α（PPAR-alpha）靶基因的mRNA水平增加，表明SCD 1-/-小鼠中脂肪酸β-氧化增加。我们假设，SCD 1缺陷诱导的信号，下调脂肪生成通过调节SREBP-1蛋白成熟和激活PPARa途径分配脂肪酸对脂肪酸β-氧化。我们将使用野生型（SCD 1 +/+）、杂合子（SCD 1 +/-）和纯合子（SCD 1-/-）小鼠以及来源于这些动物的原代肝细胞设计实验来解决这一假设。该提案的具体目标是：1.确定SCD 1缺乏是否会导致肝脏SREBP-1蛋白加工成成熟形式的障碍，并下调脂肪生成。2.阐明SCD 1缺乏如何上调脂肪酸β-氧化。 总之，我们的研究将提供硬脂酰辅酶A去饱和酶基因表达在脂质和碳水化合物代谢中的作用的生理相关信息，并将增强我们对糖尿病和肥胖症中脂肪生成和失调的代谢控制的理解。

DESCRIPTION (provided by applicant): Stearoyl-CoA desaturase is a central lipogenic enzyme catalyzing all reactions in the synthesis of monounsaturated fatty acids mainly oleate (C18:1) and palmitoleate (C16:1) which are the major monounsaturated fatty acids of membrane phospholipids, triglycerides, wax esters and cholesterol esters. Several SCD gene isoforms (SCD1, SCD2, SCD3) exist in the mouse. We have found that mice with a targeted disruption of the SCD1 isoform (SCD1-/-) have reduced body fat, plasma leptin and insulin levels and a reduced rate of triglyceride synthesis in liver. Compared to wild type mice, SCD1-/- mice are lean and resistant to high fat diet-induced obesity. The expression of lipogenic genes is reduced in the SCD1-/- mice. It is well known that fatty acid and triglyceride synthesis is regulated by the insulin-dependent gene expression and maturation of the sterol regulatory element binding protein-ic (SREBP-1c). What we found instead is that while the SREBP-1c gene expression was not altered in the SCD1-/- mice, the maturation of the SREBP-1 protein into its transcriptionally active form is blocked. The levels of ketone bodies and the mRNA levels of the peroxisome proliferator activated receptor alpha (PPAR-alpha) target genes are increased suggesting increased fatty acid Beta-oxidation in the SCD1-/- mice. We hypothesize that SCD1 deficiency induces a signal that down regulates lipogenesis by modulating the SREBP-1 protein maturation and activates the PPARa pathway to partition fatty acids towards fatty acid Beta-oxidation. We shall design experiments to address this hypothesis using wild type (SCD1 +/+), heterozygotes (SCD1+/-) and homozygotes (SCD1-/-) mice as well as primary hepatocytes derived from these animals. The specific aims of this proposal are: 1. To determine whether SCD1 deficiency causes a blockage in the processing of the liver SREBP-1 protein to its mature form and down-regulates lipogenesis. 2. To elucidate how SCD1 deficiency up-regulates fatty acid Beta-oxidation. Overall, our studies wil provide physiologically relevant information on the role of stearoyl-CoA desaturase gene expression in lipid and carbohydrate metabolism and will enhance our understanding of metabolic control of lipogenesis and dysregulation in diabetes and obesity.