Ileal Bile Acid Transporter Metabolism and Regulation

描述（由申请人提供）：本申请的目的是促进我们对肠道胆汁酸转运蛋白的生理作用及其与肠道和代谢疾病的关系的理解。胆汁酸在脂肪和脂溶性维生素的肠道吸收、肠道抗微生物防御中起关键作用，并作为信号分子调节脂质和葡萄糖代谢。胆汁酸转运蛋白通过调节肝肠循环中胆汁酸的流量，控制胆汁酸的区室化，调节其生理和病理生理作用。在上一个资助期，我们证明了有机溶质转运蛋白Ost？的重要性。奥斯特？用于维持肠肝循环和胆汁酸稳态。这项更新申请中提出的研究将集中在扩大我们对肠道胆汁酸转运蛋白的生理作用及其与肠道和代谢疾病的关系的理解。这包括确定机制，负责肠道适应性反应在奥斯特？裸小鼠，以及阻断肠道胆汁酸吸收防止高脂肪饮食诱导的肥胖和代谢综合征发展的机制。特定目的1中的研究旨在进一步阐明Ost？的体内功能。奥斯特？通过确定机制负责肠道适应性反应在奥斯特？无效小鼠。我们的研究表明，胆汁酸和脂质代谢的调节是不同的影响破坏肠胆汁酸吸收的顶膜与基底外侧膜。基于这项工作，特定目标2中的研究旨在确定回肠FGF 15表达和胆汁酸流量在与胆汁酸肠肝循环中断相关的抗肥胖和降血糖作用中的作用。这项工作的长期目标是了解胆汁酸在人类胃肠道和代谢疾病中的作用，并将这些见解转化为新的预防措施和治疗方法。

DESCRIPTION (provided by applicant): The goal of this application is to advance our understanding of the physiological roles of the intestinal bile acid transporters and their relationship to intestinal and metabolic disease. Bile acids play critical roles in the intestinal absorption of fats and fat-soluble vitamins, gut anti-microbial defenses, and as signaling molecules to modulate lipid and glucose metabolism. By regulating the flux of bile acids in the enterohepatic circulation, bile acid transporters control the compartmentalization of bile acids and modulate their physiological and pathophysiological actions. In the previous funding period, we demonstrated the importance of the Organic Solute Transporter Ost?-Ost? for maintenance of the enterohepatic circulation and bile acid homeostasis. The studies proposed in this renewal application will focus on expanding our understanding of the physiological roles of the intestinal bile acid transporters and their relationship to intestinal and metabolic disease. This includes identifying the mechanisms responsible for the intestinal adaptive response in the Ost? null mice, and the mechanisms by which blocking intestinal bile acid absorption protects against the development of high fat diet-induced obesity and metabolic syndrome. The studies in Specific Aim 1 are designed to further elucidate the in vivo functions of Ost?-Ost? by determining the mechanisms responsible for the intestinal adaptive response in Ost? null mice. Our studies demonstrated that regulation of bile acid and lipid metabolism is differentially affected by disruption of intestinal bile acid absorption at the apical versus basolateral membranes. Based on this work, the studies in Specific Aim 2 are designed to define the roles of ileal FGF15 expression and bile acid flux in the anti-obesity and hypoglycemic effects associated with interruption of the enterohepatic circulation of bile acids. The long-term goal of this work is to understand the role of bile acids in human gastrointestinal and metabolic disease, and translate those insights into new preventive measures and therapies.