Role of Stearoyl-CoA Desaturase in Metabolism

描述(由申请人提供)：硬脂酰辅酶A去饱和酶是一种中心造脂酶，催化合成单不饱和脂肪酸的所有反应，主要是油酸(C18：1)和棕榈油酸酯(C16：1)，它们是膜磷脂、甘油三酯、蜡酯和胆固醇酯的主要单不饱和脂肪酸。小鼠体内存在SCD基因的几种异构体(SCD1、SCD2、SCD3)。我们发现，靶向阻断SCD1亚型(SCD1-/-)的小鼠可以降低体脂、血浆瘦素和胰岛素水平，并降低肝脏甘油三酯合成的速度。与野生型小鼠相比，SCD1-/-小鼠更瘦，对高脂饮食诱导的肥胖具有抵抗力。在SCD1-/-小鼠中，成脂基因的表达减少。众所周知，脂肪酸和甘油三酯的合成受胰岛素依赖的基因表达和固醇调节元件结合蛋白-1c(SREBP-1c)的成熟调控。相反，我们发现，虽然SREBP-1c基因在SCD1-/-小鼠中的表达没有改变，但SREBP-1蛋白成熟为其转录活性形式的过程被阻止。酮体水平和过氧化物酶体增殖物激活受体α(PPAR-α)靶基因的mRNA水平增加，表明SCD1-/-小鼠的脂肪酸β氧化增加。我们推测，SCD1缺陷通过调节SREBP-1蛋白的成熟来诱导下调脂肪生成的信号，并激活PPARa途径将脂肪酸分配给脂肪酸β-氧化。我们将设计实验，使用野生型(SCD1+/+)、杂合子(SCD1+/-)和纯合子(SCD1-/-)小鼠以及来自这些动物的原代肝细胞来解决这一假设。这项建议的具体目的是：1.确定SCD1缺乏是否会导致肝脏SREBP-1蛋白成熟的过程受阻，并下调脂肪生成。2.阐明SCD_1缺乏对脂肪酸β-氧化的上调作用。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肪和碳水化合物代谢中的作用的生理学相关信息，并将加深我们对糖尿病和肥胖症中脂肪生成和调节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.