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: 10240659
• 负责人: DOUGLAS G BURRIN
• 金额: $ 41.11万
• 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/10240659
• 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; Intestines; Lead; Link; Lipids; Liver; Liver diseases; Maintenance; Mediating; Metabolic; 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; porcine model; 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.

这项研究的长期目标是确定肠外营养（PN）如何调节肝脏代谢功能并改变婴儿患肝病的风险。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 PN 诱导的肝病新生猪模型进行的初步研究表明，用选择性 FXR 激动剂奥贝胆酸 (OCA) 治疗可以预防 PNALD。 OCA 的保护作用与肠道和肝脏 FXR 靶基因的诱导相关，其特征是局部 FGF19 表达和循环 FGF19 增加、肝胆胆汁盐输出泵表达增加以及胆管减少症的逆转。我们还表明，新一代肠外脂肪乳剂 (SMOFlipid) 会引起肠道微生物组的显着变化，这与肝脏和肠道中 FXR 的激活相关。这一竞争性更新的总体目标是建立细胞和分子机制，通过肠外营养脂肪乳剂破坏胆汁酸稳态，并确定肝脏和肠道 FXR-FGF19 信号如何介导这些作用。我们的中心假设是，激活胆汁酸受体功能，特别是肠道和肝脏中的 FXR 和 FGF19 作用，对于预防 PNALD 是必要的。目标 1：我们将量化经肠内 OCA 或重组猪 FGF19 处理的 TPN 喂养仔猪的胆汁酸稳态和胆管结构，以测试 FGF19 是否足以预防 PNALD。我们将量化胆汁酸和 FGF19 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-FGF19 信号传导和增殖。目标 2：我们将使用来自早产仔猪的粪便微生物组移植 (FMT)，这些仔猪被给予不同的脂质乳剂，诱导或预防胆汁淤积，以测试肠道微生物群落是否足以预防 TPN 诱导的胆汁淤积。我们将测试不同供体的 FMT 对新生、早产受体猪如何塑造肠道微生物组、代谢组和肝脏代谢组。我们将对肠道内容物和肝组织进行代谢组学分析，并测试候选代谢物是否调节猪肠类和肝细胞中的 FXR 信号传导。这些研究将测试新机制，以确定正常 FXR-FGF19 信号传导的恢复如何影响临床相关的新生儿动物模型中的肝脏代谢功能和疾病。这些针对早产猪的研究具有转化性，可能会带来预防小儿肝病的新治疗策略。