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: 8459998
• 负责人: MATAM VIJAY-KUMAR
• 金额: $ 0.66万
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459998
• 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 !

描述（由申请人提供）：在世界范围内，无论是发达国家还是发展中国家，肥胖和糖尿病的发病率都在以惊人的速度增长。肠道菌群、低级别慢性炎症和代谢综合征之间的联系最近在我们和其他实验室得到了证实。具体来说，我们的研究表明小鼠缺乏toll样受体5 (TLR5)，该受体主要在肠上皮细胞中表达