Role of stearoyl CoA desaturase-1 in TLR5 KO mice colitis and metabolic syndrome

硬脂酰辅酶A去饱和酶-1在TLR5 KO小鼠结肠炎和代谢综合征中的作用

• 批准号: 8278779
• 负责人: MATAM VIJAY-KUMAR
• 金额: $ 7.34万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-17 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278779
• 关键词: Acids; Acute; Adipose tissue; Anabolism; Applications Grants; Attenuated; Automobile Driving; Bacteria; Bacterial Proteins; Cholesterol Esters; Chronic; Colitis; Crohn' s disease; Data; Developed Countries; Developing Countries; Development; Diabetes Mellitus; Diet; Dietary Essential Fatty Acid; Dietary Formulations; Disease; Embryo; Energy Metabolism; Enterohepatic Circulation; Enzymes; Epidemic; Epithelial; Exhibits; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Genetic; Germ-Free; Greater sac of peritoneum; Hepatic; Homeostasis; Hyperglycemia; Hyperinsulinism; Hyperlipidemia; Hyperphagia; Hypertension; Hypertrophy; Inflammation; Inflammatory; Inflammatory disease of the intestine; Insulin Resistance; Intestinal Content; Intestines; Knockout Mice; Laboratories; Leptin deficiency; Life Style; Link; Lipids; Liver; Liver diseases; Mentored Research Scientist Development Award; Mesentery; Metabolic; Metabolic Diseases; Metabolic syndrome; Modeling; Molecular; Monounsaturated Fatty Acids; Mus; Obesity; Oleic Acids; Overweight; Palmitates; Pathogenesis; Patients; Phenotype; Phospholipids; Play; Population; Prevention; Public Health; Publishing; Research Proposals; Role; Saturated Fatty Acids; Serum; Serum amyloid A protein; Sodium Dextran Sulfate; Stearates; Stearoyl-CoA Desaturase; Surrogate Markers; Testing; Therapeutic; Tissues; Toll-Like Receptor 5; Transplantation; Triglycerides; Twin Multiple Birth; desaturase; design; enzyme activity; feeding; gut microbiota; indexing; lipid biosynthesis; lipid metabolism; mouse model; non-alcoholic fatty liver; novel; obesity in children; overexpression; pi bond; prevent; saturated fat; statistics; stearoyl-coenzyme A; trend

DESCRIPTION (provided by applicant): Rates of obesity and diabetes are increasing at an alarming rate throughout the world, in both developed and developing countries. A link between the intestinal microbiota, low-grade chronic inflammation and metabolic syndrome has been recently established in our and other laboratories. Specifically, our studies demonstrate that mice lacking toll-like receptor 5 (TLR5), which is predominantly expressed by intestinal epithelial cels, develop spontaneous colitis because of an inability to maintain intestinal bacterial homeostasis. Further, upon rederivation of TLR5KO mice via embryonic transfer, ocurence of spontaneous colitis was substantialy reduced as was inflammation. Such low-grade inflammation in TLR5KO mice resulted in hyperglycemia, hyperlipidemia, hyperphagia, insulin resistance, obesity, hepatic steatosis and hypertension, collectively referred to as metabolic syndrome. Further experimentation with these mice indicated that an altered intestinal microbiota composition is responsible for the development of metabolic syndrome as we can transfer metabolic syndrome by transplanting cecal microbiota from TLR5KO mice to germ-free WT mice. However, the molecular mechanism for the development of metabolic syndrome is not clear. This grant proposal aims to clarify the role of lipid metabolism in the development of colits and metabolic syndrome in TLR5KO mice. Stearoyl Coenzyme A Desaturase-1 (SCD-1) synthesizes monounsaturated fatty acids (MUFA; C16:1 and C18:1) from dietary or de novo saturated fatty acids (SFA; C16:0 and C18:0). It has been proposed that SFA are highly lipotoxic and SCD-1 converts them into less toxic MUFA. These MUFA serve as precursors for the synthesis of hepatic lipids (triglycerides (TG) and cholesterol esters (CE) and thus play a role in the development of hepatic steatosis. Interestingly, SCD-1 deficiency exacerbates intestinal inflammation in an acute model of Dextran Sodium Sulfate (DSS) and C. rodentium induced colitis and SCD-1 overexpression significantly attenuated such colitis. In addition, diets rich in oleic acid protected against mouse models of colitis. Our hypothesis is that TLR5KO mice, which exhibit hyperphagia and an increased bacterial burden, generate large amounts of SFA which enter the liver via enterohepatic circulation and may be driving inflammation. Such a mechanism suggests that, to protect against lipotoxic effects of large amounts of SFA, TLR5KO mice convert them into less toxic MUFA which leads to increased hepatic lipogenesis. Our preliminary results indicate that TLR5KO mice have elevated levels of the SCD-1 product C18:1 n9 (oleic acid) in liver lipids, particularly TG and CE, supporting our hypothesis. We propose to study the role of SCD-1 in the development of colitis and metabolic syndrome by generating SCD-1/TLR5 double knockout mice. Overall, our research proposal may help in designing oleate-rich dietary formulations and also clarify whether SCD-1 can be targeted to prevent colitis and metabolic diseases ! PUBLIC HEALTH RELEVANCE: The proposed studies will demonstrate the role of a fat synthesizing enzyme in the development of spontaneous colitis, obesity and diabetes in mice deficient in recognizing a bacterial protein. Our hypothesis is that increased fat synthesis is a 'metabolic adaptation' to protect against the spontaneous inflammation that eventually results in obesity and diabetes. This study may help in designing therapeutic dietary formulations to treat inflammatory/metabolic diseases.

描述(申请人提供)：肥胖和糖尿病的比率正以惊人的速度在世界各地增长，无论是在发达国家还是发展中国家。我们和其他实验室最近确定了肠道微生物区系、低度慢性炎症和代谢综合征之间的联系。特别是，我们的研究表明，缺乏Toll样受体5(TLR5)的小鼠，TLR5主要由肠道上皮细胞表达 CEL，由于无法维持肠道细菌内环境平衡而发展为自发性结肠炎。此外，通过胚胎移植获得TLR5KO小鼠后，自发性结肠炎的发生率显著减少，炎症也减少。TLR5KO小鼠的这种低度炎症导致高血糖、高脂血症、吞噬功能亢进、胰岛素抵抗、肥胖、肝脏脂肪变性和高血压，统称为代谢综合征。对这些小鼠的进一步实验表明，肠道微生物群的变化是代谢综合征发生的原因，因为我们可以通过将盲肠微生物群从TLR5KO小鼠移植到无菌WT小鼠来转移代谢综合征。然而，代谢综合征发生的分子机制尚不清楚。这项资助提案旨在阐明脂代谢在TLR5KO小鼠结肠和代谢综合征发展中的作用。硬脂酰辅酶A脱饱和酶-1(SCD-1)从膳食或从头饱和脂肪酸(SFA；C16：0和C18：0)合成单不饱和脂肪酸(MUFA；C16：1和C18：1)。有人提出，SFA具有高度的脂毒性，SCD-1可以将它们转化为毒性较低的MUFA。这些MUFA可作为合成肝脂(甘油三酯(TG)和胆固醇酯(CE))的前体，从而在肝脏脂肪变性的发生发展中发挥作用。有趣的是，SCD-1缺乏会加重葡聚糖硫酸钠(DSS)和齿状念珠菌诱导的结肠炎的急性模型的肠道炎症，而SCD-1过表达显著减轻这种结肠炎。此外，富含油酸的饮食可以预防小鼠结肠炎模型。我们的假设是，TLR5KO小鼠表现出过度吞噬和细菌负荷增加，产生大量SFA，这些SFA通过肝肠循环进入肝脏，可能推动炎症。这一机制表明，为了保护大量SFA的脂毒性效应，TLR5KO小鼠将其转化为毒性较低的MUFA，从而导致肝脏脂肪生成增加。我们的初步结果表明，TLR5KO小鼠肝脏脂质中SCD-1产物C18：1N9(油酸)水平升高，特别是甘油三酯和CE，支持我们的假设。我们建议通过建立SCD-1/TLR5双基因敲除小鼠来研究SCD-1在结肠炎和代谢综合征发展中的作用。总体而言，我们的研究建议可能有助于设计富含油酸的饮食配方，并澄清SCD-1是否可以靶向预防结肠炎和代谢性疾病！ 公共卫生相关性：拟议的研究将证明脂肪合成酶在缺乏识别细菌蛋白质的小鼠的自发性结肠炎、肥胖和糖尿病的发展中所起的作用。我们的假设是，脂肪合成增加是一种“新陈代谢适应”，可以防止最终导致肥胖和糖尿病的自发性炎症。这项研究可能有助于设计治疗性饮食配方来治疗炎症性/代谢性疾病。