Regulation of Hepatic Metabolic Function by Parenteral Nutrition

肠外营养对肝脏代谢功能的调节

• 批准号: 10022446
• 负责人: DOUGLAS G BURRIN
• 金额: $ 31.86万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-18 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10022446
• 关键词: Acids; Affect; Agonist; Animal Model; Bile Acid Biosynthesis Pathway; Bile Acids; Bile fluid; Biliary; Birth; Cell Proliferation; Childhood; Cholestasis; Development; Disease; Duct (organ) structure; Ductal Epithelium; Effectiveness; Emulsions; Endocrine; Energy-Generating Resources; Enteral; Enteral Nutrition; Essential Fatty Acids; FGF19 gene; Family suidae; Fibroblast Growth Factor Receptors; Funding; Gene Expression; Generations; Genes; Goals; Growth; Hepatic; Hepatobiliary; Hepatocyte; Homeostasis; Hospitalization; In Vitro; Infant; Infusion procedures; Intestinal Neoplasms; Intestines; Lead; Link; Lipids; Liver; Liver diseases; Maintenance; Mediating; Metabolic; Modeling; Molecular; Neonatal; Newborn Animals; Newborn Infant; Outcome; Parenteral Nutrition; Peptides; Plasma; Production; Proteins; Publishing; Pump; Receptor Gene; Receptor Signaling; Recombinant Fibroblast Growth Factor; Recombinants; Regulation; Research; Risk; Shapes; Signal Pathway; Signal Transduction; Soybeans; Structure; Testing; Tissues; base; bile duct; bile salts; cholangiocyte; cholestatic liver disease; clinically relevant; disease phenotype; dysbiosis; fat nutrition study; fecal transplantation; gut microbiome; gut microbiota; in vivo; liver inflammation; metabolome; metabolomics; novel; novel therapeutic intervention; novel therapeutics; overexpression; paracrine; premature; prevent; receptor; receptor function; restoration

The long-term goal of this research is to establish how parenteral nutrition (PN) regulates hepatic metabolic function and alters the risk of liver disease in infants. Many infants receive PN during hospitalization and this is associated with steatosis and cholestatic liver disease (PNALD). Our preliminary studies using our neonatal pig model of PN-induced liver disease showed that treatment with the selective FXR agonist, obeticholic acid (OCA), prevented PNALD. The protective action of OCA is associated with an induction of intestinal and hepatic FXR target genes marked by increased local FGF19 expression and circulating FGF19, increased hepatobiliary bile-salt export pump expression, and reversal of biliary ductopenia. We also show that the new generation parenteral lipid emulsion (SMOFlipid) induced marked changes in the gut microbiome that correlate with activation of FXR in the liver and intestine. The overall objective of this competitive renewal is to establish cellular and molecular mechanisms whereby parenteral nutrition lipid emulsions disrupt bile acid homeostasis and to also determine how liver and intestinal FXR-FGF19 signaling mediate these actions. Our central hypothesis is that activation of bile acid receptor function, especially FXR and FGF19 action in the intestine and liver is necessary to prevent PNALD. Aim 1: We will quantify bile acid homeostasis and biliary structure in TPN-fed piglets treated with either enteral OCA or recombinant porcine FGF19 to test whether FGF19 is sufficient to prevent PNALD. We will quantify how bile acids and FGF19 regulate the expression of bile acid synthesis and transport genes in hepatoctyes and FXR-FGF19 signaling and proliferation in cholangiocytes. Aim 2: We will use fecal microbiome transplant (FMT) from preterm piglets given different lipid emulsions that induce or prevent cholestasis to test whether the gut microbial community is sufficient to prevent TPN-induced cholestasis. We will test how FMT from different donors into newborn, preterm recipient pigs shapes the gut microbiome and metabolome and liver metabolome. We will perform metabolomic profiling of gut contents and liver tissue and test whether candidate metabolites modulate FXR signaling in pig enteroids and hepatocytes. These studies will test novel mechanisms to establish how restoration of normal FXR-FGF19 signaling affects hepatic metabolic function and disease in a clinically-relevant, neonatal animal model. These studies in premature pigs are translational and may lead to new therapeutic strategies to prevent pediatric liver disease.

本研究的长期目标是确定肠外营养（PN）如何调节婴儿的肝脏代谢功能并改变肝脏疾病的风险。许多婴儿在住院期间接受PN，这与脂肪变性和胆汁淤积性肝病（PNALD）有关。我们使用我们的PN诱导的肝脏疾病的新生猪模型的初步研究表明，用选择性FXR激动剂奥贝胆酸（OCA）治疗可以预防PNALD。OCA的保护作用与肠和肝FXR靶基因的诱导相关，其特征为局部FGF 19表达和循环FGF 19增加、肝胆胆盐输出泵表达增加和胆管减少症逆转。我们还表明，新一代胃肠外脂肪乳剂（SMOFlipid）诱导了肠道微生物组的显著变化，这些变化与肝脏和肠道中FXR的激活相关。这种竞争性更新的总体目标是建立肠外营养脂肪乳剂破坏胆汁酸稳态的细胞和分子机制，并确定肝脏和肠道FXR-FGF 19信号传导如何介导这些作用。我们的中心假设是胆汁酸受体功能的激活，特别是肠和肝脏中的FXR和FGF 19作用是预防PNALD所必需的。目标1：我们将量化用肠内OCA或重组猪FGF 19处理的TPN喂养仔猪的胆汁酸稳态和胆汁结构，以测试FGF 19是否足以预防PNALD。我们将量化胆汁酸和FGF 19如何调节肝细胞中胆汁酸合成和转运基因的表达以及胆管细胞中FXR-FGF 19信号传导和增殖。目标二：我们将使用早产仔猪的粪便微生物组移植物（FMT），给予诱导或预防胆汁淤积的不同脂肪乳剂，以检测肠道微生物群落是否足以预防TPN诱导的胆汁淤积。我们将测试来自不同供体的FMT如何影响新生、早产受体猪的肠道微生物组、代谢组和肝脏代谢组。我们将对肠道内容物和肝脏组织进行代谢组学分析，并测试候选代谢物是否调节猪肠道和肝细胞中的FXR信号传导。这些研究将测试新的机制，以确定恢复正常FXR-FGF 19信号传导如何影响临床相关的新生动物模型中的肝脏代谢功能和疾病。这些在早产猪中的研究是转化的，可能会导致预防儿科肝病的新治疗策略。