Regulation of Sodium Dependent Bile Acid Absorption in Obesity

肥胖症中钠依赖性胆汁酸吸收的调节

• 批准号: 10460405
• 负责人: Subha Arthur
• 金额: $ 22.12万
• 依托单位: MARSHALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10460405
• 关键词: ASBT protein; Address; Affect; Affinity; Animal Model; Apical; Appalachian Region; Assimilations; Bile Acids; Body fat; Body mass index; Cell membrane; Cells; Country; Disease; Distal; Epidemic; Future; Genetic Transcription; Homeostasis; Human; Ileitis; Inflammatory Bowel Diseases; Intestinal Absorption; Intestines; Kinetics; Knowledge; Lipids; Malabsorption Syndromes; Malnutrition; Mediating; Modality; Modeling; Molecular; Mus; Na(+)-K(+)-Exchanging ATPase; Obesity; Obesity Epidemic; Oryctolagus cuniculus; Rattus; Regulation; Secondary to; Sodium; Steatorrhea; Taurine Cholate; Thinness; Villus; Vitamins; West Virginia; Western Blotting; Zucker Rats; absorption; basolateral membrane; brush border membrane; design; human model; ileum; in vivo Model; inhibitor; mouse model; novel; obese patients; symporter; trafficking; uptake

Altered lipid homeostasis and increased whole body fat are hallmarks of obesity which has become a national epidemic. In turn, mammalian intestinal absorption of lipids is dependent on bile acids. Bile acids themselves are reabsorbed in the distal ileum via the intestinal apical sodium-dependent bile acid co-transporter (ASBT, SC10A2) localized at the brush border membrane (BBM) of absorptive villus cells. ASBT is the sole bile acid absorptive mechanism in the human intestine. While increased lipid absorption is known in obesity, how ASBT mediated intestinal bile acid absorption may be regulate in obesity is not known. Preliminary studies in well- established in-vivo models of obesity, specifically in Obese Zucker rats and TALLYHO mice, suggest that ASBT is increased in villus cells. This is not secondary to altered Na-extruding capacity of the cell as Na-K- ATPase levels were not increased but decreased in these cells. Similar observations were seen in obese humans. Given these translationally relevant novel observations, the overall hypothesis of this proposal is that enhanced lipid absorption of obesity mediated by bile acids is facilitated by stimulation of ASBT during obesity. Therefore, the overall aim of this proposal is to determine the molecular and intracellular mechanisms of regulation of ASBT in obesity. Three specific aims will complementarily and comprehensively address this novel hypothesis: Aim 1. Determine the broad applicability of stimulation of ASBT in villus cells during obesity Aim 2. Delineate the specific transcriptional mechanism of stimulation of ASBT in villus cells. Aim 3. Determine the specific post-transcriptional mechanism of stimulation of ASBT in villus cells. The results of these studies will provide new and important knowledge of the regulation of the ASBT in obesity which may allow for the design of ASBT inhibitors that would reduce lipid absorption and decrease obesity. The novel observations of this proposal about the regulation of ASBT during obesity will provide the basis for a future R01 application, which will focus on the intracellular mechanism of regulation of ASBT stimulation as well as the alterations in ASBT in human obesity. Ultimately, better understanding of ASBT regulation in obesity will result in better treatment modalities for the obesity epidemic in this country.

改变脂质体内平衡和增加全身脂肪是肥胖的标志， 疫情反过来，哺乳动物肠道对脂质的吸收依赖于胆汁酸。胆汁酸本身 通过肠顶端钠依赖性胆汁酸共转运蛋白（ASBT， SC 10A 2）定位于吸收绒毛细胞刷状缘膜（BBM）。ASBT是唯一的胆汁酸 人体肠道的吸收机制。虽然增加脂肪吸收是已知的肥胖，如何ASBT 介导肠胆汁酸吸收在肥胖症中可能受到调节是未知的。初步研究表明， 已建立的体内肥胖模型，特别是在肥胖Zucker大鼠和TALLYHO小鼠中，表明 ASBT在绒毛细胞中增加。这不是次要的改变钠挤压能力的细胞作为Na-K- ATP酶水平不增加，但在这些细胞下降。在肥胖症患者中也观察到了类似的观察结果。 人类考虑到这些与实验相关的新观察结果，该提议的总体假设是， 通过在肥胖期间刺激ASBT促进由胆汁酸介导的肥胖的脂质吸收增强。 因此，本提案的总体目标是确定分子和细胞内机制 ASBT在肥胖症中的调节作用。三个具体目标将相辅相成地全面解决这一问题 新假设： 目标1.确定ASBT刺激在肥胖期间绒毛细胞中的广泛适用性 目标2.阐明ASBT刺激绒毛细胞的特异性转录机制。 目标3.确定ASBT刺激绒毛细胞的特异性转录后机制。 这些研究结果将为ASBT在肥胖中的调控提供新的重要知识 这可能允许ASBT抑制剂的设计，将减少脂质吸收和减少肥胖。 关于肥胖期间ASBT调节的这一提议的新观察将为以下研究提供基础： 未来的R 01应用，将集中在ASBT刺激调节的细胞内机制， 以及人类肥胖中ASBT的改变。最终，更好地了解ASBT法规， 肥胖症将导致更好的治疗模式，肥胖症的流行在这个国家。