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

描述（由申请人提供）：在发达国家和发展中国家，肥胖症和糖尿病的发病率在全世界以惊人的速度增加。肠道微生物群，低度慢性炎症和代谢综合征之间的联系最近已经在我们和其他实验室中建立。具体地说，我们的研究表明，缺乏Toll样受体5（TLR 5）的小鼠，主要由肠上皮细胞表达， 结肠炎，发展为自发性结肠炎，因为无法维持肠道细菌的体内平衡。此外，在通过胚胎移植再衍生TLR 5 KO小鼠后，自发性结肠炎的发生与炎症一样显著减少。TLR 5 KO小鼠中的这种低度炎症导致高血糖症、高脂血症、暴食症、胰岛素抵抗、肥胖症、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，改变的肠道微生物群组成是代谢综合征发展的原因，因为我们可以通过将盲肠微生物群从TLR 5 KO小鼠移植到无菌WT小鼠来转移代谢综合征。然而，代谢综合征发生发展的分子机制尚不清楚。这项资助提案旨在阐明脂质代谢在TLR 5 KO小鼠结肠炎和代谢综合征发展中的作用。 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具有高度脂毒性，SCD-1将其转化为毒性较低的MUFA。这些MUFA作为肝脂质（甘油三酯（TG）和胆固醇酯（CE））合成的前体，因此在肝脂肪变性的发展中发挥作用。有趣的是，在右旋糖酐硫酸钠（DSS）和C.啮齿动物诱导的结肠炎和SCD-1过表达显著减弱了这种结肠炎。此外，富含油酸的饮食可以防止小鼠结肠炎模型。我们的假设是，TLR 5 KO小鼠，表现出摄食过度和细菌负荷增加，产生大量的SFA，通过肠肝循环进入肝脏，并可能驱动炎症。这种机制表明，为了防止大量SFA的脂毒性作用，TLR 5 KO小鼠将其转化为毒性较小的MUFA，这导致肝脏脂肪生成增加。我们的初步结果表明，TLR 5 KO小鼠在肝脏脂质中具有升高水平的SCD-1产物C18：1 n9（油酸），特别是TG和CE，支持我们的假设。我们拟通过建立SCD-1/TLR 5双基因敲除小鼠模型，研究SCD-1在结肠炎和代谢综合征发病中的作用。总的来说，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是否可以预防结肠炎和代谢疾病！

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 !