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: 7414063
• 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/7414063
• 关键词: ADD-1 protein; Address; Antibodies; Applications Grants; Burn injury; Carbohydrates; Carnitine; Cholesterol Esters; Co-Immunoprecipitations; Diabetes Mellitus; Diet; Disease; Disruption; 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; Oleate; 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; Thinking; Tissues; Transferase; Transgenic Organisms; Triglycerides; Waxes; acyl-CoA dehydrogenase; base; 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）：该提案的目的是揭示分子机制，通过这些机制，stearoyl-COA去饱和酶（SCD）表达分区在储存和氧化之间呈脂质。了解脂质稳态的基础是制定新的策略来打击肥胖，糖尿病和其他异常脂质代谢疾病的基础。 SCD是一种催化单不饱和脂肪酸的合成的中心酶，主要是Oleate（C18：1），这是甘油三酸酯，胆固醇酯，蜡酯和磷脂的主要单不饱和脂肪酸。先前的批准应用中的研究表明，SCD1同工型（SCD1 - / - ）靶向破坏的小鼠脂肪生成基因表达降低，脂肪酸氧化增加并增强胰岛素敏感性。 SCD1 - / - 小鼠比对照小鼠更精细，对饮食和瘦素缺乏诱导的肥胖症具有抗药性，并降低了肝脏脂肪变性。 SCD1缺乏引起上述表型的机制仍然鲜为人知。我们最近观察到，尽管含无碳水化合物脂肪的饮食喂养SCD1 - / - 小鼠血浆胰岛素增加，但过氧化物酶体增生剂激活受体Y共激活剂（PGC-1A）的基因表达增加了，包括脂肪酸B-氧化和葡萄糖基因在喂养状态下增加了。此外，成熟的固醇调节元件结合蛋白-1（SREBP-1）的表达不会增加，并且未诱导SREBP-1C靶基因的表达。有趣的是，Inig-2a的基因表达和蛋白质水平，这种蛋白质通过将其保留在ER中，通常会因胰岛素而抑制SREBP的成熟。小鼠肝脏中人类SCD表达的转基因增加了成熟的SREBP-1蛋白和脂肪生成基因的表达。我们假设细胞18：1/18：0比率通过调节PGC-1A和Insig-2a蛋白的表达来调节餐后状态的肝脂质代谢。我们将设计实验，以使用体内和体外方法解决这一假设。该提案的两个具体目的是：1。测试肝脏SCD1缺乏是否会通过调节PGC-1A的表达来增加餐后状态中线粒体脂肪酸B氧化。 2。为了测试肝脏SCD1缺乏是否阻止SREBP-1处理并下降通过增加Insig-2a表达来调节餐后状态的脂肪生成。一餐后的脂肪储存是饮食诱发肥胖和2型糖尿病的主要原因之一。我们发现了一种机制，可以将脂肪从存储中划分为在美联储状态的燃烧。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。