The role of intestinal SCD1 in regulating metabolic health

肠道正在成为一个调节和信号器官，使饮食来源的营养素发挥作用， 必要的行动。更好地了解肠道对全身脂质代谢的调节具有直接的意义 对多种人类代谢病理学的影响，包括心血管疾病、脂肪肝和胰岛素 阻力δ-9去饱和酶，硬脂酰-CoA去饱和酶-1（SCD 1），将饱和脂肪酸转化为 单不饱和产物，并已显示调节肝脏和皮肤中的脂质酯化。然而，在这方面， 几乎没有人知道SCD 1在肠道中的作用，其中脂质酯化对于其在肠道中的作用至关重要。 最终吸收并分泌到乳糜微粒（CM）中。为了解决这一知识差距，我们生成了 仅在肠上皮细胞中靶向缺失SCD 1的小鼠（iKO小鼠）。值得注意的是，我们发现， iKO动物不仅肠道脂质显著降低，而且循环和肝脏脂质也显著降低 水平，特别是单不饱和脂肪酸的水平。iKO小鼠在这两个方面也有显著增加， 能量消耗和葡萄糖耐量，伴有棕色脂肪中产热标志物增加 组织和增加的血浆GLP-1水平。出乎意料的是，肠道SCD 1缺失升高了血浆和 肝胆汁酸（BA）和改变标志物的肝胆BA流出和回肠BA再摄取。支持 根据这些以及其他令人信服的初步数据，本应用将评估肠道SCD 1在以下方面的作用： 整合源自肠道的代谢信号。本申请的中心假设是， SCD 1通过改变分泌的脂质含量和组成、BAT中的TGR 5信号传导来调节代谢健康 和肠道以及肠肝BA代谢。这一假设将由我们的两个相关的，但 独立的具体目标。在目标1中，我们将测试肠道SCD 1抑制与能量平衡的相关性。 在高热量和高血脂饮食的背景下。我们还将评估TGR 5在以下方面的机制作用： 介导iKO小鼠代谢表型的改善。在目标2中，我们将评估SCD 1衍生的 MUFAs调节肝脏BA流出和肠道BA再摄取。我们还将利用a）抑制剂， 肠BA再摄取，B）肠限制性FXR激动剂，和c）饮食MUFA，以恢复肝脏和血浆 iKO小鼠中的BA水平。

The intestine is emerging as a regulatory and signaling organ, enabling diet-derived nutrients to perform essential actions. A better understanding of intestinal regulation of systemic lipid metabolism has direct implications to multiple human metabolic pathologies, including cardiovascular disease, fatty liver, and insulin resistance. The delta-9 desaturase, stearoyl-CoA desaturase-1 (SCD1), converts saturated fatty acids to monounsaturated products and has been shown to regulate lipid esterification in liver and skin. However, virtually nothing is known about the role of SCD1 in the intestine, where lipid esterification is crucial for its eventual absorption and secretion into chylomicrons (CMs). To address this gap in knowledge, we generated mice with a targeted deletion of SCD1 only in intestinal epithelial cells (iKO mice). Remarkably, we find that iKO animals have significant reductions not only in intestinal lipids, but also in circulating and hepatic lipid levels, particularly in levels of monounsaturated fatty acids. iKO mice also have significant increases in both energy expenditure and glucose tolerance, accompanied by increased thermogenic markers in brown adipose tissue and increased plasma GLP-1 levels. Unexpectedly, intestinal SCD1 deletion elevates plasma and hepatic bile acids (BAs) and alters markers of hepatobiliary BA efflux and ileal BA reuptake. Supported by these and other compelling preliminary data, this application will assess the role of intestinal SCD1 in integrating metabolic signals originating in the gut. The central hypothesis of this application is that intestinal SCD1 regulates metabolic health by altering secreted lipid content and composition, TGR5 signaling in BAT and the gut, and enterohepatic BA metabolism. This hypothesis will be tested by our two related but independent Specific Aims. In Aim 1, we will test the relevance of intestinal SCD1 inhibition to energy balance in the context of hypercaloric and hyperlipidemic diets. We will also evaluate a mechanistic role for TGR5 in mediating the improved metabolic phenotypes of iKO mice. In Aim 2, we will evaluate a role for SCD1-derived MUFAs in regulating hepatic BA efflux and intestinal BA reuptake . We will also utilize a) an inhibitor of intestinal BA reuptake, b) a gut-restricted FXR agonist, and c) dietary MUFAs to restore hepatic and plasma BA levels in iKO mice.