Regulation of Hepatic Metabolic Function by Parenteral Nutrition

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。我们用我们的新生猪PN诱导的肝病模型进行的初步研究表明，选择性FXR激动剂--乙酰胆酸(OCA)的治疗可以预防PNALD。OCA的保护作用与诱导肠道和肝脏FXR靶基因的表达有关，表现为局部FGF19表达和循环FGF19表达增加，肝胆盐输出泵表达增加，以及胆管减少的逆转。我们还发现，新一代肠外脂肪乳剂(SMOFlide)诱导了肠道微生物群的显著变化，这些微生物群与肝脏和肠道中FXR的激活有关。这次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-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FXR和FGF19在肠道和肝脏的作用是预防PNALD所必需的。目的1：我们将定量测定肠内注射OCA或重组猪FGF19处理的TPN喂养仔猪的胆汁酸稳态和胆汁结构，以测试FGF19是否足以预防PNALD。我们将量化胆汁酸和FGF19如何调节胆汁酸合成和转运基因在肝细胞中的表达，以及FXR-FGF19信号和胆管细胞的增殖。目的：采用早产仔猪粪便微生物组移植(FMT)的方法，给早产仔猪注射不同的诱导或预防胆汁淤积的脂肪乳剂，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捐赠者的FMT对新生、早产受体猪的肠道微生物组、代谢组和肝脏代谢组的影响。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道和肝细胞中的FXR信号。这些研究将测试新的机制，以确定恢复正常的FXR-FGF19信号如何在临床相关的新生儿动物模型中影响肝脏代谢功能和疾病。这些在早产猪身上的研究是翻译的，可能会导致预防儿科肝病的新治疗策略。

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.