Role of Stearoyl-CoA Desaturase in Metabolism

硬脂酰辅酶A去饱和酶在代谢中的作用

• 批准号: 7625072
• 负责人: JAMES M. NTAMBI
• 金额: $ 26.56万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7625072
• 关键词: ADD-1 protein; Address; Antibodies; Applications Grants; Burn injury; Carbohydrates; Carnitine; Cholesterol Esters; Co-Immunoprecipitations; Diabetes Mellitus; Diet; Disease; Energy Metabolism; Engineering; Enzymes; Esters; Exhibits; Fat-Free Diets; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Gene Expression; Gene Targeting; Genes; Genetic; Hepatic; Hepatocyte; Homeostasis; Human; In Vitro; Insulin; Insulin Resistance; Leptin deficiency; Lipids; Liver; Measures; Membrane Proteins; Messenger RNA; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Monitor; Monounsaturated Fatty Acids; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Peroxisome Proliferator-Activated Receptors; Phenotype; Phosphoenolpyruvate Carboxylase; Phospholipids; Plasma; Process; Protein Isoforms; Proteins; Research; Resistance; Role; SRE-1 binding protein; Stearoyl-CoA Desaturase; Testing; Thermogenesis; Tissues; Transferase; Transgenic Organisms; Triglycerides; Waxes; acyl-CoA dehydrogenase; base; combat; design; fatty acid oxidation; feeding; in vivo; insulin sensitivity; lipid biosynthesis; lipid metabolism; mutant; oxidation; palmitoleate; research study; transcription factor

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.

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）表达将脂质在储存和氧化之间划分的分子机制。了解脂质稳态的基础是制定对抗肥胖、糖尿病和其他脂质代谢异常疾病的新策略的基础。SCD是催化单不饱和脂肪酸合成的中心酶，主要是油酸（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。先前拨款申请中的研究表明，靶向破坏SCD1异构体（SCD1-/-）的小鼠可降低脂质基因表达，增加脂肪酸氧化并增强胰岛素敏感性。SCD1-/-小鼠比对照组小鼠更瘦，对饮食和瘦素缺乏引起的肥胖都有抵抗力，并且肝脏脂肪变性减少。SCD1缺陷引起上述表型的机制仍然知之甚少。我们最近观察到，尽管饲喂高碳水化合物无脂饮食的SCD1-/-小鼠血浆胰岛素增加，但在喂食状态下，过氧化物酶体增殖物激活受体y共激活因子（PGC-1a）的基因表达增加，包括脂肪酸b氧化和糖异生基因。成熟的甾醇调节元件结合蛋白1 （SREBP-1）的表达没有增加，SREBP-1c靶基因的表达也没有被诱导。有趣的是，insg -2a的基因表达和蛋白质水平增加，insg -2a是一种通过将SREBPs保留在内质网中来阻止其成熟的蛋白质，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蛋白和脂质基因的表达。我们假设细胞18:1/18:0的比例通过调节PGC-1a和insg -2a蛋白的表达来调节餐后状态下肝脏脂质代谢。我们将设计实验来解决这一假设，使用体内和体外的方法。这一建议的两个具体目标是：1。通过调节PGC-1a的表达，检测肝脏SCD1缺乏是否会增加餐后状态下线粒体脂肪酸b氧化。2. 目的检测肝SCD1缺乏是否通过增加insg -2a的表达，阻断SREBP-1的加工并下调餐后状态下的脂肪生成。餐后脂肪的储存是饮食性肥胖和2型糖尿病的主要原因之一。我们已经发现了一种机制，可以将脂肪从储存中分离出来，在储备状态下燃烧。我们的研究将有助于治疗人类肥胖、糖尿病和其他代谢疾病。