Fatty Acid Transport in the Intestine

脂肪酸(FA)和单酰基甘油(MG)是三酰甘油(TG)的水解物，提供 饮食能量的主要来源。然而，在理解基本原则方面仍然存在很大差距 MG和FA的同化机制。这些包括对个体的分子水平的理解 两种高表达的肠细胞脂肪酸结合蛋白(FABP)的功能 肝脏FABP。此外，MG和FA的不同转运机制增加了根尖 (AP)与肠细胞的基底外侧(BL)极，其中AP脂更高地结合到TG中， 而BL脂转化为磷脂，目前还不清楚。在这项提案中，我们将使用综合方法来 阐述肠道FA和MG转运的细胞和分子机制 和代谢，以及两种肠道细胞FABP在FA转运、脂质代谢和 脂蛋白分泌。进一步，我们将探索单酰甘油脂肪酶的调节和功能。 (MGL)，我们最近发现它在大鼠肠道中表达。具体目标是：1) 确定IFABP和LFABP在FA和MG细胞转运和代谢中的作用： 模型系统的结构-功能研究，apo-和holo-LFABP三级结构的分析，以及 将野生型和特异性FABP突变形式的蛋白质直接转移到培养的Caco-2肠细胞中 允许我们确定IFABP和LFABP各自的功能，以及它们的结构基础 2)确定FA和MG在脑内代谢区划的细胞基础。 内脏细胞。在大鼠、小鼠、特定酶和转运蛋白缺失以及Caco-2细胞中进行的研究将允许 美国将研究质膜转运蛋白、细胞内FABP和特定细胞内FABP的作用 酶，在这种代谢分化的潜在机制；和3)探索肠道的作用 单酰甘油脂肪酶，在啮齿类动物和培养细胞中的研究表明，MGL在新生儿肠道和 在成年动物中下降到较低的水平，因此我们将检查在 MGL表达式。这项研究计划的最终目的是了解如何控制速度和 通过调节特定的运输和代谢过程，饮食中脂肪同化的程度。是这样的 调节对肥胖、糖尿病和高脂血症的治疗具有重要意义。 绩效SI-E(S)(组织、市、州) 1.罗格斯大学营养科学系，新泽西州新不伦瑞克 2.纽约城市大学斯塔滕岛学院，化学系，纽约 3.罗格斯大学化学与生物化学系，新泽西州纽瓦克 关键人员。请参阅说明。 从首席调查员开始。列表 名字 朱迪思·斯托奇博士。 苏尼塔·切鲁卡博士。 杰西·加布里尔，B.S. 萨拉拉·科杜库拉，B.S. 尹子舟 露丝·E·斯塔克博士。 理查德·门德尔松博士。 马哈茂德·侯赛因博士 Nada Abumrad，博士。 路易斯·阿格隆，博士。 苏珊·K·弗里德 披露许可声明。 *PHS 398(05/01版) 根据需要使用连续页提供所需的信息 所有其他关键人员按字母顺序，姓氏在前。 组织 罗格斯大学 罗格斯大学 罗格斯大学 罗格斯大学 罗格斯大学 纽约市立大学 罗格斯大学 纽约州立大学，下州 纽约州立大学石溪分校 加拿大阿尔伯塔大学 罗格斯大学 格式如下所示。 在项目中的角色 首席调查员 博士后。联想 研究生助教 高级研究技术员 研究技术员 协作者/分包合同 协作者 协作者 协作者 协作者 协作者 仅适用于SBtR/STTR。请参阅说明。[]是[]否 第2页__表第2页？ [PrincipInavlestigator/PDroirgercat(omLrasfitr，stm，Del]：斯托奥，朱迪思 必须在每张印刷页和每张续页的顶部提供首席调查员/项目主任的姓名， 研究补助金 目录 页码 主页........................................................................................................................1 描述，

Fatty acids (FA) and monoacylglycerol (MG), the hydrolytic products of triacylglycerol (TG), provide a major source of dietary energy. Nevertheless, substantial gaps remain in understanding the basic mechanisms of MG and FA assimilation. These include a molecular level understanding of the individual functions of two highly expressed enterocyte fatty acid-binding proteins (FABP), intestinal FABP and liver FABP. In addition, the mechanisms of differential trafficking of MG and FA added to the apical (AP) vs. basolateral (BL) poles of the enterocyte, where AP lipid is more highly incorporated into TG, and BL lipid into phospholipid, are not understood. In this proposal, we will use an integrated approach to address the cellular and molecular mechanisms that underlie the polarity of intestinal FA and MG transport and metabolism, and the specific roles of the two enterocyte FABPs in FA transport, lipid metabolism, and lipoportein secretion. Further, we will explore the regulation and function of monoacylglycerol lipase (MGL), which we have recently shown to be expressed in rat intestine. The specific aims are 1) To determine the functions of IFABP and LFABP in cellular transport and metabolism of FA and MG: Structure-function studies in model systems, analysis of the apo- and holo-LFABP tertiary structures, and direct protein transfer of wild type and specific FABP mutant forms into cultured Caco-2 enterocytes, will allow us to determine the individual functions of IFABP and LFABP, and the structural basis for these functional properties; 2) To determine the cellular basis for metabolic compartmentation of FA and MG in the entcrocyte. Studies in rats, mice null for specific enzymes and transport proteins, and Caco-2 cells, will allow us to examine the role of plasma membrane transporters, intracellular FABPs, and specific intracellular enzymes, in the underlying mechanisms of this metabolic divergence; and 3) To explore the role of intestinal monoacylglycerol lipase, using studies in rodents and cultured cells, MGL is higher in neonatal intestine and declines to lower levels in the adult animal, thus we will examine the mechanisms that underlie changes in MGL expression. The ultimate aim of this research program is to understand how to control the rate and extent of dietray lipid assimilation by modulating specific transport and metabolic processes. Such modulation has important implications for the treatment of obesity, diabetes, and hyperlipidemias. PERFORMANCE SI-_E(S) (organization, city, state) 1. Rutgers University, Department of Nutritional Sciences, New Brunswick, NJ 2. City University of New York, College of Staten Island, Department of Chemistry, NY 3. Rutgers University, Department of Chemistry & Biochemistry, Newark, NJ KEY PERSONNEL. See instructions. Start with Principal Investigator. List Name Judith Storch, Ph.D. Sunita Cheruka, Ph.D. Jesse Gabriel, B.S. Sarala Kodukula, B.S. Yin Ziu Zhou Ruth E. Stark, Ph.D. Richard Mendelsohn, Ph.D. Mahmood Hussein, Ph.D. Nada Abumrad, Ph.D. Luis Agellon, Ph.D. Susan K. Fried Disclosure Permission Statement. ¿ PHS 398 (Rev. 05/01) Use continuation pages as needed to provide the required information in all other key personnel in alphabetical order, last name first. Organization Rutgers University Rutgers University Rutgers University Rutgers University Rutgers University City University of New York Rutgers University State University of New York, Downstate State University of New York, Stony Brook University of Alberta, Canada Rutgers University the format shown below. Role on Project Principal Investigator Postdoc. Associate Graduate Res. Assistant Sr. Research Technician Research Technician Collaborator/subcontract Collaborator Collaborator Collaborator Collaborator Collaborator Applicable to SBtR/STTR Only. See instructions. [] Yes [] No Page 2__ Form Page 2 ¿ ¿ PrincipInavlestigator/PDroirgercat(omLrasfitr,stm, iddle): Storoh, Judith The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page, RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page .................................................................................................................................................. 1 Description,