SREBP-Mediated Lipid Regulation in the Intestine

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。控制低密度脂蛋白摄取和胆固醇合成的关键因素被称为固醇反应元件结合蛋白，或SREBP。我的导师布朗和戈尔茨坦在1993年发现了SREBP，并在随后的几年里描述了细胞如何开启和关闭SREBP。SREBP受另外两个因素控制，分别为Scap和Insig。Scap和Insig检测细胞中的胆固醇水平。当胆固醇高时，Insigs阻断Scap并防止SREBP被激活。当胆固醇低时，Insigs的阻断作用丧失，Scap激活SREBP，使它们能够打开合成脂质或从血液中摄取LDL胆固醇所需的所有基因。 虽然所有的器官都能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。我们的实验室几年前就表明，当肝脏中的SREBP功能不正常时，它会导致高血胆固醇。胆固醇在小肠中的调节是 不太了解。肠的内层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性合成和LDL摄取胆固醇外，它们还从饮食中吸收胆固醇。很大一部分脂质 最终在身体其他地方的蛋白质来源于肠上皮细胞，它们是新合成的或从食物中吸收的。因此，肠道在胆固醇稳态的控制中至关重要，因此旨在了解肠道生物学和NIDDK支持的代谢控制的研究具有深远的意义。 我最近的研究是第一次研究SREBP在肠上皮细胞中的功能，结果表明SREBP提供了小肠胆固醇的关键控制。本提案的目的是在这些研究的基础上进行扩展，并概述了一项使用转基因小鼠的计划，在该计划中，我将在肠道中释放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它们的后果来了解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：血液中过量的脂质或高脂血症会导致心脏病发作。肝脏中的脂质过多，或脂肪肝疾病，会导致肝硬化。脂肪组织中过量的脂质，或肥胖，会导致大量的健康问题。通过打开或关闭同样患有高脂血症、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。最终目标是确定是否可以利用阻断肠道中的SREBP来开发对抗高脂血症、脂肪肝和肥胖的新药。

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.