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

肠胆汁酸，Fxr，

• 批准号: 8697069
• 负责人: GRACE L GUO
• 金额: $ 28.24万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-05 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697069
• 关键词: Bile Acid Biosynthesis Pathway; Bile Acids; Binding; Cholestasis; Chromatin; Clinic; Complication; Development; Emulsions; Endocrine; Enteral Feeding; Enterohepatic Circulation; Enzymes; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Future; Gene Expression; Goals; Hepatic; Hepatocyte; Homeostasis; Human; Intestines; Ligands; Lipids; Liver; Liver diseases; MAPK Signaling Pathway Pathway; Measures; Mediating; Metabolism; Minor; Molecular; Mus; Nuclear Receptors; Nutrient; Operative Surgical Procedures; Pancreatic Diseases; Pathway interactions; Patients; Physiological; Play; Positioning Attribute; Premature Infant; Prevention; Production; Proteins; Reagent; Regulation; Research; Role; Signal Pathway; Signal Transduction; Small Intestines; Specificity; Testing; Therapeutic; Total Parenteral Nutrition; Transgenic Mice; Travel; Work; activating transcription factor; base; design; feeding; gain of function; improved; insight; liver function; liver injury; mouse model; novel; novel therapeutics; prevent; proctolin; public health relevance; receptor; receptor function; response; small heterodimer partner protein; theories; therapy development; tool

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.

描述(申请人提供)：全肠外营养(TPN)被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。长期的TPN与严重的并发症TPN相关性胆汁淤积症(TPN-AC)有关。TPN-AC的发病机制尚不清楚。任何试图深入了解TPN-AC病因的分子机制的努力都可能使我们找到一种方法来防止它在未来的发生。胆汁酸的公开产生对肝脏有害，需要严格控制胆汁酸的平衡。最重要的机制是通过核受体超家族的配体激活的转录因子法尼醇X受体(FXR)来调节胆汁酸的动态平衡。我们和其他人已经证明，在小鼠中，肠道FXR的激活诱导小肠成纤维细胞生长因子15(Fgf15)通过抑制编码胆汁酸合成限速酶Cyp7a1的基因表达来抑制胆汁酸的合成。相反，肝脏中FXR的激活会诱导小异二聚体伙伴(SHP)，而SHP在抑制Cyp7a1基因表达方面只起到很小的作用。在理解肠道因子介导的肝脏胆汁酸合成调节的关键作用方面，这种范式转变也在人类肝细胞中得到证实。因此，肠道胆汁酸/FXR/Fgf15通路可能是TPN-AC发生和治疗的基础。本研究的目的是确定肠道胆汁酸/FXR/Fgf15通路在小鼠TPN-AC发生和治疗中的作用，以期为人类提供一种新的治疗策略。我推测，TPN-AC的机制是TPN增加胆汁酸的合成和破坏肠-肝循环，导致胆汁淤积，继而失去肠道胆汁酸/FXR/Fgf15通路的激活；通过向肠道补充胆汁酸、重新激活肠道FXR或在TPN期间应用外源性Fgf15来重新建立这一途径，可能预防和/或治疗TPN-AC。提出了三个独立但又相互关联的目标，以在小鼠身上检验这一新假设。目的1.综合表征TPN对胆汁酸平衡的破坏作用，确定胆汁酸合成在TPN-AC发展中的作用，并验证补充肠道胆汁酸是否能预防和/或治疗TPN-AC。目的2.确定TPN对肠道FXR功能的影响，并检测再次激活肠道FXR在多大程度上预防或治疗TPN-AC。目的3.探讨Fgf15在TPN-AC防治中的作用。我们以前的工作为理解肠道胆汁酸/FXR/Fgf15途径抑制肝脏胆汁酸合成的机制提供了一个范式转变。这项建议一旦完成，将为理解TPN-AC的发病机制(S)提供一个新颖而关键的科学基础，并可能对未来TPN-AC的预防和/或治疗设计新的治疗策略产生巨大影响。