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

肠胆汁酸，Fxr，

• 批准号: 9066738
• 负责人: GRACE L GUO
• 金额: $ 27.77万
• 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 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9066738
• 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; Knockout Mice; 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; Therapy trial; 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; 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（由申请人提供）：总肠胃外营养（TPN）被广泛用于为无法忍受肠内喂养的患者提供营养，包括早产儿，小蛋黄手术患者或胰腺疾病的患者。长期TPN与严重的并发症，与TPN相关的胆汁淤积（TPN-AC）有关。 TPN-AC原因的基本机制知之甚少。任何努力洞悉TPN-AC原因的分子机制，都可能使我们能够开发出一种防止其未来发生的方法。胆汁酸的明显产生对肝脏有毒，需要严格调节胆汁酸稳态。最重要的机制是调节胆汁酸稳态是由属于核受体超家族Farnesoid X受体（FXR）的配体激活的转录因子（FXR）药物。我们和其他人表明，在小鼠中，肠道FXR的激活在小肠中诱导成纤维细胞生长因子15（FGF15），通过抑制CYP7A1的基因表达来抑制胆汁酸合成，从而编码胆汁酸合成中速率限制酶的基因表达。相反，FXR在肝脏中的激活诱导小型异二聚体伴侣（SHP），这仅在抑制CYP7A1基因表达中起较小的作用。在人类肝细胞中也证实了肠道因子介导的胆汁酸合成调节的关键作用的这种范式转变。因此，肠道胆汁酸/FXR/FGF15途径可能是TPN-AC原因和治疗的基本基础。该提案的目的是确定小鼠肠胆汁酸/FXR/FGF15途径在小鼠TPN-AC发育和治疗中的作用，以便在人类中提供一种新颖的治疗策略。我假设TPN-AC的机制是因为在失去肠道胆汁酸/FXR/FXR/FGF15途径之后，TPN的胆汁酸合成和肠肝循环的破坏会导致胆汁淤积。通过将胆汁酸补充为肠道，重新激活肠道FXR或在TPN期间给予外源性FGF15来重新建立这一途径。提出了三个独立但相互关联的目的来检验小鼠中的这种新假设。 AIM 1。全面地表征TPN胆汁酸稳态的破坏，确定胆汁酸合成对TPN-AC发育的贡献，并测试是否补充肠胆酸预防和/或治疗TPN-AC。 AIM 2。确定TPN对肠道FXR功能的影响，并测试肠道FXR预防或治疗TPN-AC的程度重新激活。目标3。确定FGF15在预防和治疗TPN-AC中的作用。我们以前的工作为理解肠胆酸/FXR/FGF15途径抑制胆汁酸合成的机制提供了范式转移。该提案一旦完成，将为理解TPN-AC原因的机制提供新颖而关键的科学基础，并可能对在未来的预防和/或治疗TPN-AC方面设计新型的治疗策略产生巨大影响。