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维持胆汁酸肠肝循环、调节胆汁酸流量和防止胆汁酸诱导损伤的转运途径的理解。这一建议的基础是我们最近鉴定的异聚有机溶质转运蛋白，Osta-Ostb，作为肠道胆汁酸转运的主要机制。在本申请中，我们将重点关注支持Osta-Ostb维持胆汁酸稳态的机制以及Osta-Ostb在肠和结肠上皮中的细胞保护作用。我们以前的研究表明，肠道胆汁酸吸收受损，但没有取消在Osta-/-小鼠。基于这些发现，特定目的1中的研究旨在检验ABC转运蛋白Mrp 3和Mrp 4负责残留胆汁酸转运并用于保护回肠上皮免受Osta敲除小鼠中胆汁酸诱导的损伤的假设。我们的研究表明，Osta-Ostb的表达密切受底物调节，以平衡胆汁酸流量和细胞内浓度。因此，Osta-Ostb表达的失调可能显著改变胆汁酸和脂质代谢，强调了最近发现的胆结石患者回肠中OSTa-OSTb表达降低的重要性。我们的工作表明，胆汁酸合成的调节在Osta-/-小鼠中发生了深刻的改变。基于这些观察结果，特定目标2中的研究旨在阐明Osta敲除小鼠中胆汁酸稳态改变的机制。在结肠中，内源性细菌植物群将胆汁酸转化为能够被动扩散到上皮细胞中的更疏水的种类。然而，很少有人知道的机制从事输出胆汁酸和保护结肠细胞免受胆汁酸诱导的损害。我们的初步数据表明，Osta-/-小鼠更容易受到葡聚糖硫酸钠诱导的结肠损伤相比，同窝对照。这些发现强调了最近观察到的OSTa表达在溃疡性结肠炎患者的结肠中显著降低的重要性。基于这些发现，特定目的3中的研究旨在检验Osta-Ostb负责结肠基底外侧胆汁酸转运并保护结肠免受胆汁酸细胞毒性作用的假设。这项工作的长期目标是了解控制胆汁酸区室化和肝肠循环的机制及其与人类胃肠道和代谢疾病的关系。 公共卫生相关性：胆汁酸在脂肪和脂溶性维生素的肠吸收中、在肠道抗微生物防御中以及作为调节脂质和葡萄糖代谢的信号分子起关键作用。然而，胆汁酸也具有细胞毒性，并促进肝损伤、肠道炎症和胃肠道癌症。该提案中的研究将为人体如何控制胆汁酸的区室化提供新的见解，并促进这些肝脏和胃肠道疾病的新疗法的开发。

DESCRIPTION (provided by applicant): The goal of this application is to advance our understanding of the transport pathways that maintain the enterohepatic circulation of bile acids, regulate bile acid flux, and protect against bile acid-induced injury. The foundation for this proposal is our recent identification of the heteromeric Organic Solute Transporter, Osta-Ostb, as a major mechanism for intestinal bile acid transport. In this application, we will focus on the mechanisms that support Osta-Ostb to maintain bile acid homeostasis and on the cytoprotective role of Osta-Ostb in the intestinal and colonic epithelium. Our previous studies demonstrated that intestinal bile acid absorption is impaired but not abolished in Osta-/- mice. Based on those findings, the studies in Specific Aim 1 are designed to test the hypothesis that the ABC transporters Mrp3 and Mrp4 are responsible for the residual bile acid transport and serve to protect the ileal epithelium from bile acid-induced damage in the Osta null mice. Our studies demonstrated that expression of Osta-Ostb is closely regulated by substrate to balance the bile acid flux and intracellular concentration. As such, dysregulation of Osta-Ostb expression may significantly alter bile acid and lipid metabolism, underscoring the importance of the recent finding that OSTa-OSTb expression is decreased in ileum from gallstone patients. Our work showed that the regulation of bile acid synthesis is profoundly altered in Osta-/- mice. Based on these observations, the studies in Specific Aim 2 are designed to elucidate the mechanisms responsible for the altered bile acid homeostasis in the Osta null mice. In the colon, the endogenous bacterial flora convert bile acids to more hydrophobic species capable of passively diffusing into epithelial cells. However, little is known about the mechanisms engaged to export bile acids and protect the colonocyte against bile acid-induced damage. Our preliminary data suggest that Osta-/- mice are more susceptible to dextran sodium sulfate-induced colonic injury as compared to littermate controls. These findings underscore the importance of the recent observation that OSTa expression is dramatically reduced in colon from patients with ulcerative colitis. Based on these findings, the studies in Specific Aim 3 are designed to test the hypothesis that Osta-Ostb is responsible for colonic basolateral bile acid transport and functions to protect the colon from the cytotoxic effects of bile acids. The long-term goal of this work is to understand the mechanisms that control the compartmentalization and enterohepatic circulation of bile acids and their relationship to human gastrointestinal and metabolic disease. PUBLIC HEALTH RELEVANCE: Bile acids play critical roles in intestinal absorption of fats and fat-soluble vitamins, in gut anti- microbial defenses, and as signaling molecules to modulate lipid and glucose metabolism. However, bile acids are also cytotoxic and promote hepatic injury, intestinal inflammation, and gastrointestinal cancers. The studies in this proposal will provide new insights as to how the body controls the compartmentalization of bile acids and promote the development of new therapies for these hepatic and gastrointestinal disorders.