SREBP-Mediated Lipid Regulation in the Intestine

SREBP 介导的肠道脂质调节

• 批准号: 8917213
• 负责人: Luke James Engelking
• 金额: $ 14.72万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8917213
• 关键词: Address; Adipose tissue; Animals; Binding; Binding Proteins; Biology; Blood; Carbohydrates; Cardiovascular Diseases; Cells; Cessation of life; Cholesterol; Cholesterol Homeostasis; Cirrhosis; Complex; Development; Diet; Dietary Cholesterol; Disease; Dyslipidemias; Endoplasmic Reticulum; Enterocytes; Enzymes; Family; Fatty Liver; Feedback; Food; Genes; Genetic; Goals; Golgi Apparatus; Grant; Health; Hepatic; Homeostasis; Hydroxymethylglutaryl-CoA reductase; Hyperlipidemia; Hypertriglyceridemia; Insulin Resistance; Intestines; Knowledge; LDL Cholesterol Lipoproteins; Laboratories; Lead; Lipid Synthesis Pathway; Lipids; Liver; Liver diseases; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Mediating; Membrane; Membrane Proteins; Mentors; Metabolic syndrome; Metabolism; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; Names; National Institute of Diabetes and Digestive and Kidney Diseases; Nuclear; Obesity; Organ; Pathogenesis; Pathologic; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Plasma; Play; Proteins; Proteolysis; Regulation; Research; Response Elements; Role; SRE-2 binding protein; Site; Small Intestines; Sterols; Stress; Therapeutic Agents; Tissues; Triglycerides; United States; Work; activating transcription factor; cholesterol control; cholesterol transporters; combat; drug development; ezetimibe; hypercholesterolemia; in vivo; insight; interest; lipid disorder; lipid metabolism; mortality; mouse model; non-alcoholic fatty liver; novel; novel therapeutics; prevent; response; site-1 protease; transcription factor; uptake

DESCRIPTION (provided by applicant): High cholesterol diets raise the level of Low Density Lipoprotein (LDL) cholesterol in blood and produce heart attacks, thereby causing one-third of all deaths in the United States. The key factors that control LDL uptake and cholesterol synthesis are called sterol response element binding proteins, or SREBPs. My mentors, Brown and Goldstein, discovered SREBPs in 1993 and in the intervening years described how cells turn on and off SREBPs. SREBPs are controlled by two other factors, named Scap and Insig. Scap and Insig sense cholesterol levels in the cell. When cholesterol is high, Insigs block Scap and prevent SREBPs from being activated. When cholesterol is low, the blocking effect of Insigs is lost and Scap activates SREBPs so that they can turn on all of the genes needed to synthesize lipids or take up LDL cholesterol from the blood. Although all organs are capable of cholesterol synthesis and LDL uptake, the most important organs are the liver and small intestine. Our laboratory showed years ago that when SREBPs in the liver are not functioning properly it can lead to high blood cholesterol. Regulation of cholesterol in the small intestine is poorly understood. The interior lining of the intestines is made from cells called enterocytes. They are unique in that, in addition to getting cholesterol from endogenous synthesis and LDL uptake as do all other cells, they also absorb cholesterol from the diet. A large portion of lipids that end up elsewhere in the body originated in enterocytes, where they were newly synthesized or absorbed from food. Therefore, the intestine is critically important in the control of cholesterl homeostasis, and so the research aimed at understanding intestinal biology and the control of metabolism supported by the NIDDK has far-reaching implications. My recent studies were the first to look at SREBP function in enterocytes, and the results indicated that SREBPs provide key control of cholesterol in the small intestines. The aims of this proposal expands on these studies and outline a plan using genetically modified mice in which I will inactivate Insig (causin SREBP activation) or Scap (causing SREBP inactivation) in the intestine. The primary goal is to understand the function of SREBPs in the intestines by examining the consequences of turning them on or off. The second goal is to determine whether lipid synthesis in the intestines contributes to the buildup of lipids in other tissues associated with certain diseases: excess lipi in the blood, or hyperlipidemia, causes heart attacks. Excess lipid in the liver, or fatty liver disease, causes cirrhosis. Excess lipid in adipose tissue, or obesity, causes a huge number of health problems. By turning on or off SREBPs in the intestines of mice that also have hyperlipidemia, obesity, or fatty liver, we will find out if SREBPs contribute to these diseases. The ultimate goal is to determine if blocking SREBPs in the intestine can be employed to develop new drugs to combat hyperlipidemia, fatty liver, and obesity.

描述（由申请人提供）：高胆固醇饮食会提高血液中低密度脂蛋白（LDL）胆固醇的水平并导致心脏病发作，从而导致美国三分之一的死亡。控制 LDL 摄取和胆固醇合成的关键因素称为甾醇反应元件结合蛋白 (SREBP)。我的导师 Brown 和 Goldstein 在 1993 年发现了 SREBP，并在随后的几年中描述了细胞如何打开和关闭 SREBP。 SREBP 受另外两个因素控制，即 Scap 和 Insig。 Scap 和 Insig 感知细胞中的胆固醇水平。当胆固醇水平较高时，Insigs 会阻断 Scap 并防止 SREBP 被激活。当胆固醇较低时，Insigs 的阻断作用就会消失，Scap 会激活 SREBP，以便它们可以开启合成脂质或从血液中吸收 LDL 胆固醇所需的所有基因。 尽管所有器官都能够合成胆固醇和摄取低密度脂蛋白，但最重要的器官是肝脏和小肠。我们的实验室多年前就表明，当肝脏中的 SREBP 不能正常工作时，可能会导致高血液胆固醇。小肠中胆固醇的调节是 不太了解。肠的内壁由称为肠上皮细胞的细胞组成。它们的独特之处在于，除了像所有其他细胞一样从内源合成和低密度脂蛋白摄取中获取胆固醇外，它们还从饮食中吸收胆固醇。很大一部分脂质 最终到达身体其他部位的物质起源于肠细胞，在那里它们是新合成的或从食物中吸收的。因此，肠道对于胆固醇稳态的控制至关重要，因此NIDDK支持的旨在了解肠道生物学和代谢控制的研究具有深远的意义。 我最近的研究首次关注了肠上皮细胞中的 SREBP 功能，结果表明 SREBP 对小肠中的胆固醇起到了关键的控制作用。该提案的目的扩展了这些研究，并概述了一项使用转基因小鼠的计划，其中我将在肠道中灭活 Insig（导致 SREBP 激活）或 Scap（导致 SREBP 失活）。主要目标是通过检查打开或关闭 SREBP 的后果来了解 SREBP 在肠道中的功能。第二个目标是确定肠道中的脂质合成是否会导致与某些疾病相关的其他组织中的脂质积聚：血液中脂质过多或高脂血症会导致心脏病发作。肝脏中脂质过多或脂肪肝疾病会导致肝硬化。脂肪组织中过多的脂质或肥胖会导致大量的健康问题。通过打开或关闭患有高脂血症、肥胖或脂肪肝的小鼠肠道中的 SREBP，我们将发现 SREBP 是否会导致这些疾病。最终目标是确定阻断肠道中的 SREBP 是否可以用于开发治疗高脂血症、脂肪肝和肥胖的新药。