The role of intestinal SCD1 in regulating metabolic health

肠道SCD1在调节代谢健康中的作用

基本信息

批准号：
10297251
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
项目类别：
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/10297251
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/antagonist intestinal epithelium lipid metabolism lipidomics metabolic phenotype mouse model novel receptor reuptake uptake virtual

项目摘要

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.

肠道正在成为一个调节和信号器官，使饮食中的营养素能够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意义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，硬脂酰辅酶 A 去饱和酶-1 (SCD1)，将饱和脂肪酸转化为单不饱和产品，已被证明可以调节肝脏和皮肤中的脂质酯化。然而，事实上，我们对 SCD1 在肠道中的作用一无所知，其中脂质酯化对于其发挥作用至关重要。最终吸收并分泌成乳糜微粒（CM）。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删除 SCD1 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着降低，循环脂质和肝脏脂质也显着降低水平，特别是单不饱和脂肪酸的水平。 iKO 小鼠的两项指标均显着增加能量消耗和葡萄糖耐量，伴随着棕色脂肪中产热标记物的增加组织和血浆 GLP-1 水平升高。出乎意料的是，肠道 SCD1 缺失使血浆和肝胆汁酸 (BA) 并改变肝胆 BA 流出和回肠 BA 再摄取的标志物。支持者这些和其他令人信服的初步数据，该应用程序将评估肠道 SCD1 在整合源自肠道的代谢信号。本申请的中心假设是肠道 SCD1 通过改变 BAT 中分泌的脂质含量和成分、TGR5 信号传导来调节代谢健康以及肠道和肠肝 BA 代谢。这个假设将由我们的两个相关但独立的具体目标。在目标 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血症饮食的情况下。我们还将评估 TGR5 在以下方面的机械作用：介导 iKO 小鼠代谢表型的改善。在目标 2 中，我们将评估 SCD1 衍生的作用 MUFA 调节肝脏 BA 流出和肠道 BA 再摄取。我们还将利用 a) 抑制剂肠道 BA 再摄取，b) 肠道限制性 FXR 激动剂，以及 c) 膳食 MUFA 以恢复肝脏和血浆 iKO 小鼠的 BA 水平。