Role of Stearoyl-CoA Desaturase in Metabolism

描述（申请人提供）：硬脂酰辅酶a去饱和酶是一种中心脂肪生成酶，催化合成单不饱和脂肪酸的所有反应，主要是油酸酯（C18:1）和棕榈油酸酯（C16:1），这是膜磷脂、甘油三酯、蜡酯和胆固醇酯的主要单不饱和脂肪酸。SCD基因的几种亚型（SCD1、SCD2、SCD3）存在于小鼠体内。我们发现，靶向破坏SCD1异构体（SCD1-/-）的小鼠体内脂肪、血浆瘦素和胰岛素水平降低，肝脏中甘油三酯合成率降低。与野生型小鼠相比，SCD1-/-小鼠更瘦，对高脂肪饮食引起的肥胖有抵抗力。SCD1-/-小鼠的脂肪生成基因表达降低。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（SREBP-1c）成熟的调控。我们发现，虽然SCD1-/-小鼠的SREBP-1c基因表达没有改变，但SREBP-1蛋白成熟为转录活性形式的过程被阻断。酮体水平和过氧化物酶体增殖体激活受体α (ppar - α)靶基因mRNA水平升高，提示SCD1-/-小鼠脂肪酸β -氧化增加。我们假设SCD1缺乏通过调节SREBP-1蛋白成熟诱导一个下调脂肪生成的信号，并激活PPARa途径将脂肪酸分割成脂肪酸β氧化。我们将使用野生型（SCD1+/ +）、杂合子（SCD1+/-）和纯合子（SCD1-/-）小鼠以及来源于这些动物的原代肝细胞来设计实验来验证这一假设。本建议的具体目的是：1。确定SCD1缺乏是否会导致肝脏SREBP-1蛋白向成熟形态的加工受阻，并下调脂肪生成。2. 阐明SCD1缺乏如何上调脂肪酸β -氧化。总之，我们的研究将提供有关硬脂酰辅酶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学相关信息，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.