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.

脂质稳态改变和全身脂肪增加是肥胖的标志，这已成为国家 流行性。反过来，脂质的哺乳动物肠道吸收取决于胆汁酸。胆汁酸本身 通过肠道顶钠依赖性胆汁酸共转运蛋白（ASBT，，ASBT， SC10A2）位于吸收性绒毛细胞的刷子边界膜（BBM）。 ASBT是唯一的胆汁酸 人类肠的吸收机制。虽然肥胖症中已知脂质吸收增加，但ASBT如何 在肥胖症中可能调节介导的肠胆汁酸的吸收。良好的初步研究 建立的肥胖体内模型，特别是在肥胖的Zucker大鼠和Tallyho小鼠中，表明 绒毛细胞中的ASBT增加。这不是次要改变细胞为Na-k-的NA击退能力的继发性。 这些细胞中的ATPase水平没有升高，但降低了。在肥胖中看到了类似的观察 人类。鉴于这些翻译相关的新颖观察结果，该提议的总体假设是 肥胖期间的ASBT刺激促进了胆汁酸介导的肥胖的脂质吸收。 因此，该提案的总体目的是确定分子和细胞内机制 肥胖症中ASBT的调节。三个具体目标将在互补和全面解决这个问题 新假设： 目标1。确定肥胖期间绒毛细胞中ASBT刺激的广泛适用性 AIM 2。描述绒毛细胞中ASBT刺激的特定转录机制。 AIM 3。确定绒毛细胞中ASBT刺激的特定转录后机制。 这些研究的结果将为肥胖症中ASBT的调节提供新的重要知识 这可能允许设计ASBT抑制剂，以减少脂质吸收并降低肥胖症。 关于肥胖期间ASBT调节的这一提议的新发现，将为A提供基础 未来的R01应用，该应用将集中于ASBT刺激调节的细胞内机制 以及人类肥胖症中ASBT的改变。最终，更好地理解ASBT监管 肥胖症将导致该国肥胖流行的更好治疗方式。