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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：全世界，无论是发达国家还是发展中国家，肥胖和糖尿病的发病率正在以惊人的速度增加。我们和其他实验室最近建立了肠道微生物群、低度慢性炎症和代谢综合征之间的联系。具体来说，我们的研究表明，小鼠缺乏 Toll 样受体 5 (TLR5)，该受体主要由肠上皮细胞表达由于无法维持肠道细菌稳态，细胞会发展为自发性结肠炎。此外，通过胚胎移植重新衍生 TLR5KO 小鼠后，自发性结肠炎和炎症的发生率大大减少。 TLR5KO小鼠的这种低度炎症导致高血糖、高脂血症、食欲亢进、胰岛素抵抗、肥胖、肝脂肪变性和高血压，统称为代谢综合征。对这些小鼠的进一步实验表明，肠道微生物群组成的改变是代谢综合征发生的原因，因为我们可以通过将 TLR5KO 小鼠的盲肠微生物群移植到无菌 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。该拨款提案旨在阐明脂质代谢在 TLR5KO 小鼠结肠炎和代谢综合征发生中的作用。硬脂酰辅酶 A 去饱和酶-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 具有高脂毒性，而 SCD-1 将其转化为毒性较低的 MUFA。这些 MUFA 作为合成肝脂质（甘油三酯 (TG) 和胆固醇酯 (CE)）的前体，因此在肝脂肪变性的发展中发挥作用。有趣的是，SCD-1 缺乏会加剧葡聚糖钠急性模型中的肠道炎症硫酸盐 (DSS) 和啮齿类动物 C. rodentium 诱导的结肠炎和 SCD-1 过度表达显着减轻了这种结肠炎。此外，富含油酸的饮食。我们的假设是，表现出食欲亢进和细菌负荷增加的 TLR5KO 小鼠会产生大量的 SFA，这些 SFA 通过肠肝循环进入肝脏，并可能导致炎症。为了对抗大量 SFA 的脂毒性作用，TLR5KO 小鼠将其转化为毒性较小的 MUFA，从而导致肝脏脂肪生成增加。我们的初步结果表明，TLR5KO 小鼠的 SCD-1 产物水平升高。肝脏脂质中的 C18:1 n9（油酸），特别是 TG 和 CE，支持了我们的假设。我们建议通过生成 SCD-1/TLR5 双敲除小鼠来研究 SCD-1 在结肠炎和代谢综合征发展中的作用。总的来说，我们的研究计划可能有助于设计富含油酸的膳食配方，并阐明 SCD-1 是否可以有针对性地预防结肠炎和代谢性疾病！