SREBP-Mediated Lipid Regulation in the Intestine

SREBP 介导的肠道脂质调节

• 批准号: 8751584
• 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/8751584
• 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; public health relevance; response; site-1 protease; transcription factor; uptake; 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; public health relevance; 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）：高胆固醇饮食提高了血液中低密度脂蛋白（LDL）胆固醇的水平，并引起心脏病发作，从而导致美国所有死亡的三分之一。控制LDL摄取和胆固醇合成的关键因素称为固醇反应元件结合蛋白或SREBPS。我的导师布朗（Brown）和戈德斯坦（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SREBPS。 SREBP由另外两个因素控制，称为SCAP和Insig。 SCAP和INSIG感知细胞中的胆固醇水平。当胆固醇较高时，Insigs会阻止SCAP并防止SREBP被激活。当胆固醇较低时，损失的促进效应会丢失并激活SREBPS，以便它们可以打开合成脂质或从血液中吸收LDL胆固醇所需的所有基因。 尽管所有器官均能够合成胆固醇和LDL摄取，但最重要的器官是肝脏和小肠。我们的实验室表明，几年前，当肝脏中的SREBP无法正常运行时，可能会导致高血胆固醇。小肠中胆固醇的调节是 理解不佳。肠的内衬由称为肠上皮细胞的细胞制成。它们是独一无二的，除了从内源性合成和LDL摄取的胆固醇和所有其他细胞中获得胆固醇外，它们还从饮食中吸收胆固醇。大部分脂质 最终在体内的其他地方起源于肠球细胞，在那里它们是新合成或从食物中吸收的。因此，肠道在控制胆固醇稳态方面至关重要，因此旨在理解NIDDK支持的肠生物学和对代谢的控制的研究具有深远的影响。 我最近的研究是第一个研究肠球细胞中SREBP功能的研究，结果表明SREBPS在小肠中提供了胆固醇的关键控制。该提案的目的扩大了这些研究，并使用转基因的小鼠概述了一项计划，其中我将在肠道中灭活Insig（Causin srebp激活）或SCAP（引起SREBP失活）。主要目标是通过检查打开或关闭的后果来了解SREBPS在肠中的功能。第二个目标是确定肠中的脂质合成是否有助于与某些疾病相关的其他组织中脂质的积累：血液中过量的LIPI或高脂血症会导致心脏病发作。肝脏或脂肪肝病中的脂质过多会导致肝硬化。脂肪组织或肥胖症中过量的脂质会导致大量健康问题。通过在还具有高脂血症，肥胖或脂肪肝的小鼠肠道中打开或关闭SREBP，我们将确定SREBPs是否有助于这些疾病。最终目标是确定是否可以使用肠中的SREBP来开发新药来打击高脂血症，脂肪肝和肥胖。