STEAROYL-COA DESATURASE-1 IN SKELET AL MUSCLE LIPID ACCUMULATN & INSULIN RESIST

骨骼肌脂质积累中的硬脂酰辅酶 A 去饱和酶 1

• 批准号: 7382262
• 负责人: MATTHEW W HULVER
• 金额: $ 22.54万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-04 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382262
• 关键词: enzymes; fatty acids; human; insulin; insulin sensitivity /resistance; lipids; metabolism; muscle; muscle cells; oxidation; striated muscles

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Stearoyl-CoA desaturase-1 (SCD1) is a lipogenic enzyme that catalyzes the synthesis of monounsaturated fatty acids, which are the predominate fatty acids of triacylglycerols. Mice with a targeted disruption of SCO 1 (SCD1-/-) have reduced adiposity, increased insulin sensitivity, and reduced levels of hepatic triacylglycerols. Additionally, in SCD1-/- mice, hepatic expression of genes encoding enzymes of fatty acid oxidation and lipid synthesis is up regulated and down regulated, respectively. Skeletal muscle of obese humans is insulin resistant, possesses reduced rates of fatty acid (FA) oxidation, and elevated lipid content, all of which occurs in concert with an upregulation of SCD1. Functional implications of these findings were tested by overexpressing SCD1 in primary human myocytes from nonobese subjects, which resulted in altered fatty acid partitioning by increasing IMTG accumulation and inhibiting mitochondrial b-oxidation.The overall hypothesis of this proposal is that an upregulation of SCDl in skeletal muscle of obese humans causes lipid accumulation and insulin resistance. This hypothesis will be tested using human in vivo, in vitro, and cell culture research models. The objectives of this proposal are to: 1) examine relationships between in vitro measures of skeletal muscle FA metabolism, skeletal muscle SCDl activity, and in vivo measures of wholebody insulin sensitivity; 2) over express and knockdown SCDl gene transcription in primary human myocytes cultured from nonobese and obese humans, respectively, and examine substrate metabolism (FA and glucose) and insulin signaling; and 3) discern the mechanism(s) by which elevated SCDl actwity results in intramuscular lipid accumulation. Overall, the proposed studies will provide physiologically relevant information on the role of SCDl in skeletal muscle lipid accumulation and insulin resistance in humans. Understanding the mechanism(s) responsible for intramuscular lipid accumulation is essential for developing pharmacological treatments that could abolish this disorder.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。硬脂酰辅酶A去饱和酶-1 (SCD1) 是一种脂肪生成酶，可催化单不饱和脂肪酸的合成，单不饱和脂肪酸是三酰甘油的主要脂肪酸。靶向破坏 SCO 1 (SCD1-/-) 的小鼠脂肪减少，胰岛素敏感性增加，肝三酰甘油水平降低。此外，在SCD1-/-小鼠中，编码脂肪酸氧化酶和脂质合成酶的基因的肝脏表达分别上调和下调。肥胖人群的骨骼肌具有胰岛素抵抗性、脂肪酸 (FA) 氧化率降低和脂质含量升高，所有这些都与 SCD1 的上调同时发生。这些发现的功能意义是通过在非肥胖受试者的原代人类肌细胞中过度表达 SCD1 来测试的，这通过增加 IMTG 积累和抑制线粒体 b-氧化而导致脂肪酸分配的改变。该提议的总体假设是，肥胖人骨骼肌中 SCD1 的上调会导致脂质积累和胰岛素抵抗。该假设将使用人体体内、体外和细胞培养研究模型进行测试。该提案的目的是：1)检查骨骼肌FA代谢、骨骼肌SCD1活性的体外测量值和全身胰岛素敏感性的体内测量值之间的关系； 2)分别在非肥胖和肥胖人类培养的原代人类肌细胞中过表达和敲低SCD1基因转录，并​​检查底物代谢（FA和葡萄糖）和胰岛素信号传导； 3)辨别升高的SCD1活性导致肌内脂质积累的机制。总体而言，所提出的研究将提供关于SCD1在人类骨骼肌脂质积累和胰岛素抵抗中的作用的生理学相关信息。了解肌肉内脂质积累的机制对于开发可以消除这种疾病的药物治疗至关重要。