Gut bile acids, Fxr, & Fgf15 in total parenteral nutrition-associated cholestasis

描述（由申请方提供）：全肠外营养（TPN）广泛用于向不能耐受肠内喂养的患者提供营养，包括早产儿、小肠手术患者或胰腺疾病患者。长期TPN与严重并发症TPN相关胆汁淤积（TPN-AC）相关。人们对主题方案网络-活性炭的成因机制知之甚少。任何对TPN-AC病因的分子机制的深入研究都可能使我们能够开发出一种预防其发生的方法。胆汁酸的明显产生对肝脏是有毒的，并且胆汁酸稳态需要严格调节。最重要的机制是调节胆汁酸稳态是由属于核受体超家族的配体激活的转录因子，法尼醇X受体（Fxr）。我们和其他人已经表明，在小鼠中，肠道Fxr的激活诱导小肠中的成纤维细胞生长因子15（Fgf 15）通过抑制编码胆汁酸合成限速酶Cyp 7a 1的基因表达来抑制胆汁酸合成。相反，肝脏中Fxr的激活诱导小异源二聚体伴侣（Shp），其在抑制Cyp 7a 1基因表达中仅起次要作用。这种理解肠道因子介导的肝脏胆汁酸合成调控的关键作用的范式转变也已在人肝细胞中得到证实。因此，肠道胆汁酸/Fxr/Fgf 15通路可能是TPN-AC病因和治疗的基础。本提案的目的是确定肠道胆汁酸/Fxr/Fgf 15途径在小鼠TPN-AC开发和治疗中的作用，以便为人类提供新的治疗策略。我假设TPN-AC的病因机制是TPN导致胆汁酸合成增加和肝肠循环破坏，导致胆汁淤积，随后肠道胆汁酸/Fxr/Fgf 15通路活化丧失;通过补充肠道胆汁酸、重新激活肠道Fxr或在TPN期间给予外源性Fgf 15来重建该通路可能预防和/或治疗TPN-AC。提出了三个独立但相互关联的目标来测试小鼠的这一新假设。目标1。全面表征TPN对胆汁酸稳态的破坏，确定胆汁酸合成对TPN-AC发展的贡献，并测试补充肠道胆汁酸是否预防和/或治疗TPN-AC。目标二。确定TPN对肠道Fxr功能的影响，并测试肠道Fxr的重新激活在多大程度上预防或治疗TPN-AC。目标3：确定Fgf 15在预防和治疗TPN-AC中的作用。我们以前的工作提供了一个范式的转变，在理解的机制，抑制胆汁酸合成在肝脏中的肠道胆汁酸/Fxr/Fgf 15途径。该提案一旦完成，将为理解TPN-AC病因的机制提供新的和关键的科学依据，并可能对设计未来预防和/或治疗TPN-AC的新治疗策略产生巨大影响。

DESCRIPTION (provided by applicant): Total parenteral nutrition (TPN) is widely used to supply nutrients to patients who cannot tolerate enteral feeding, including premature infants, patients with small-bowel surgery, or patients with pancreatic diseases. Long-term TPN is associated with a severe complication, TPN-associated cholestasis (TPN-AC). The mechanism underlying the cause of TPN-AC is poorly understood. Any effort to gain insight into the molecular mechanism of TPN-AC cause may allow us to develop a way to prevent its occurrence in future. Overt production of bile acids is toxic to livers and bile acid homeostasis needs to be tightly regulated. The most important mechanism is regulating bile acid homeostasis is medicated by a ligand-activated transcription factor belonging to the nuclear receptor superfamily, farnesoid X receptor (Fxr). We and others have shown that in mice, activation of intestinal Fxr induces fibroblast growth factor 15 (Fgf15) in the small intestine to suppress bile acid synthesis by inhibiting the gene expression of Cyp7a1 that encodes the rate-limiting enzyme in bile acid synthesis. In contrast, activation of Fxr in the liver induces small heterodimer partner (Shp), which only plays a minor role in inhibiting Cyp7a1 gene expression. This paradigm shift in understanding critical roles of gut factor-mediated regulation of bile acid synthesis in the liver has also been confirmed in human hepatocytes. Therefore, the intestinal bile acids/Fxr/Fgf15 pathway may be a fundamental basis for TPN-AC cause and treatment. The objective of this proposal is to determine the role of the intestinal bile acids/Fxr/Fgf15 pathway in TPN-AC development and treatment in mice, in order to provide a novel therapeutic strategy in humans. I hypothesize that the mechanism of TPN-AC cause is that increased bile acid synthesis and disruption of enterohepatic circulation by TPN leads to cholestasis, following loss of activation of the intestine bile acids/Fxr/Fgf15 pathway; re-establishing this pathway by replenishing bile acids into the gut, re-activation of intestinal Fxr or administering exogenous Fgf15 during TPN may prevent and/or treat TPN-AC. Three independent but inter-related aims are proposed to test this novel hypothesis in mice. Aim 1. Comprehensively characterize the disruption of bile acid homeostasis by TPN, determine the contribution of bile acid synthesis to TPN-AC development, and test whether replenishing gut bile acids prevent and/or treat TPN-AC. Aim 2. Determine the effects of TPN on intestinal Fxr function, and test to what degree re-activation of gut Fxr prevents or treats TPN-AC. Aim 3. Determine the role of Fgf15 in the prevention and treatment of TPN-AC. Our previous work has provided a paradigm shift in understanding the mechanism of suppressing bile acid synthesis in the liver by the gut bile acids/Fxr/Fgf15 pathway. This proposal, once completed, will provide a novel and critical scientific basis in understanding the mechanism(s) of TPN-AC cause, and likely have a huge impact on designing novel therapeutic strategies in future prevention and/or treatment of TPN-AC.