The role of intestinal SCD1 in regulating metabolic health

肠道SCD1在调节代谢健康中的作用

• 批准号: 10430276
• 负责人: Harini Sampath
• 金额: $ 39.16万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10430276
• 关键词: Acids; Acute; Address; Agonist; Animals; Assimilations; Bile Acids; Bile fluid; Biliary; Brown Fat; Caco-2 Cells; Cardiovascular Diseases; Cell Line; Cholesterol; Chylomicrons; Data; Development; Diet; Energy Metabolism; Enterocytes; Epithelial Cells; Esterification; Fatty Acids; Fatty Liver; G-Protein-Coupled Receptors; GPBAR1 gene; Gene Expression; Health; Hepatic; Hepatobiliary; Homeostasis; Human; Hyperlipidemia; Insulin Resistance; Intestinal Content; Intestines; Knowledge; Link; Lipids; Lipoproteins; Liver; LoxP-flanked allele; Measurement; Measures; Mediating; Metabolic; Monounsaturated Fatty Acids; Mus; Mutation; Nutrient; Nutritional; Oral Administration; Organ; Pathology; Peroxisome Proliferator-Activated Receptors; Pharmacologic Substance; Plasma; Proteins; Receptor Signaling; Regulation; Role; SIRT1 gene; Saturated Fatty Acids; Signal Transduction; Skin; Stearoyl-CoA Desaturase; Sucrose; Testing; Tissues; absorption; bile acid metabolism; cardiometabolism; dietary; energy balance; feeding; glucagon-like peptide 1; glucose metabolism; glucose tolerance; improved; inhibitor; intestinal epithelium; lipid metabolism; lipidomics; metabolic phenotype; mouse model; novel; receptor; reuptake; uptake; virtual

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.

肠道正在作为调节性和信号器官出现，使饮食衍生的营养素能够执行 基本行动。更好地了解全身脂质代谢的肠道调节已直接 对多种人类代谢病理的影响，包括心血管疾病，脂肪肝和胰岛素 反抗。 Delta-9去饱和酶，stearoyl-COA去饱和酶-1（SCD1），将饱和脂肪酸转化为 单不饱和产物，已被证明可以调节肝脏和皮肤中的脂质酯化。然而， 几乎对SCD1在肠中的作用几乎一无所知，在肠道中，脂质酯化至关重要 最终吸收和分泌到乳糜微粒（CMS）中。为了解决知识的差距，我们产生了 仅在肠上皮细胞（IKO小鼠）中具有靶向缺失的小鼠。值得注意的是，我们发现 IKO动物不仅在肠脂质中显着减少，而且在循环和肝脂质中也有显着降低 水平，特别是在单不饱和脂肪酸的水平。 IKO小鼠的两者也有显着增加 能量消耗和葡萄糖耐受性，伴随着棕色脂肪中的热标记增加 组织和等离子体GLP-1水平增加。出乎意料的是，肠道SCD1缺失提高了血浆和 肝胆汁酸（BAS）和肝素BA外排和伊利尔BA再摄取的标记。支持 这些和其他引人入胜的初步数据，该应用将评估肠道SCD1在 整合源自肠道的代谢信号。该应用的中心假设是肠道 SCD1通过改变分泌的脂质含量和成分，TGR5信号传导来调节代谢健康 和肠道和肠肝的代谢。该假设将由我们的两个相关的测试，但 独立的特定目的。在AIM 1中，我们将测试肠道SCD1抑制与能量平衡的相关性 在高热量和高脂饮食的背景下。我们还将评估TGR5在 介导了IKO小鼠的改善代谢表型。在AIM 2中，我们将评估SCD1衍生的角色 在调节肝BA外排和肠道BA再摄取中的MUFA。我们还将利用a） 肠道BA再摄取，b）肠道限制的FXR激动剂，c）饮食中恢复肝和等离子体 IKO小鼠的BA水平。