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: 8502096
• 负责人: DOUGLAS G BURRIN
• 金额: $ 27.77万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502096
• 关键词: Acids; Affect; Agonist; Animal Model; Bile Acid Biosynthesis Pathway; Bile Acids; Bilirubin; Biochemical Markers; Birth; CYP7A1 gene; Chenodeoxycholic Acid; Child; Childhood; Cholestasis; Disease; Dose; Emulsions; Energy-Generating Resources; Enteral; Enteral Nutrition; Essential Fatty Acids; Family suidae; Fat emulsion; Fatty Acids; Fatty Liver; Feedback; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Fish Oils; Functional disorder; Gene Expression; Gene Targeting; Generations; Genes; Goals; Hepatic; Hepatocyte; Histopathology; Homeostasis; Hospitalization; Individual; Infant; Inflammation; Intestines; Kinetics; Lead; Life; Lipids; Liver; Liver diseases; Measures; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Neonatal; Newborn Animals; Nutritional Support; Palmitates; Parenteral Nutrition; Phytosterols; Plasma; Prevention; Regulation; Research; Research Design; Risk; Serum; Serum Markers; Signal Transduction; Soybean Oil; Soybeans; Specificity; Testing; Therapeutic; Tissues; Total Parenteral Nutrition; base; clinical practice; clinically relevant; fat nutrition study; feeding; in vivo; lipid metabolism; liver injury; mRNA Expression; metabolomics; novel; novel therapeutics; oxidation; premature; prevent; public health relevance; receptor; receptor function; soy; transcriptomics

DESCRIPTION (provided by applicant): The long-term goal of this research is to establish how parenteral lipid nutrition regulates hepatic metabolic function and alters the risk of liver disease in infants. Infants given total parenteral nutrition (TPN) have increased risk for metabolic liver diseases. Our preliminary studies in premature piglets show that TPN enriched with phytosterols and n-6 fatty acids (FA) induces hepatic cholestasis, steatosis and inflammation compared to enteral nutrition. TPN also suppresses plasma FGF19, a product of farnesoid X receptor (FXR), and treatment with an FXR-agonist reverses cholestasis in TPN-fed piglets. Our central hypotheses is that parenteral lipid nutrition devoid of phytosterols and enriched with n-3 vs. n-6 FA and will prevent the TPN- associated hepatic cholestasis and steatosis in premature TPN-fed piglets via activation of FXR. AIM 1 will test whether parenteral lipid nutrition devoid of phytosterols prevents hepatic metabolic dysfunction independent of lipid load TPN-fed premature pigs. We will use in vivo metabolic (13C-bile acid turnover and 13C-palmitate oxidation kinetics) and liver transcriptomic and metabolomic approaches to systematically quantify metabolic pathways in hepatic bile acid and lipid metabolism. RNAseq analysis and metabolomic profiling will be used to identify differential expression of potentially novel hepatic genes and gene networks. Aim 2 will test whether phytosterols present in parenteral soybean-lipid emulsions induce cholestasis and metabolic liver disease via antagonism of FXR receptor function. We will measure 13C-bile acid turnover kinetics, serum biochemical markers, liver histopathology, and tissue expression of FXR and FXR target genes, especially CYP7A1, involved in bile acid metabolism. We will use hepatocytes to measure expression of FXR activity and establish the specificity of the molecular mechanisms using individual phytosterols as well as an agonist and antagonist of FXR. AIM 3 will test whether intestinal FGF19 secretion stimulated by natural and novel FXR- selective bile-acids prevents TPN-induced cholestasis by feedback regulation of FXR and CYP7A1 signaling. We will measure 13C-bile acid turnover kinetics, serum markers, liver histopathology, and tissue expression of FXR, FGF19, CYP7A1 and target genes involved in bile acid metabolism. We will use piglet hepatocytes cultures to measure mRNA expression of FXR target genes and FGF receptor-4 signaling in the presence of FGF19, phytosterols and different the lipid emulsions. These studies will test novel mechanisms to establish whether phytosterols in parenteral lipid nutrition adversely affect hepatic metabolic function and disease in a clinically-relevant, neonata animal model. These studies in premature pigs are highly translational and will lead to new clinical practices in nutritional support and prevention of liver disease in infants.

描述（由申请人提供）：本研究的长期目标是确定肠外脂质营养如何调节婴儿肝脏代谢功能和改变肝脏疾病的风险。给予全肠外营养（TPN）的婴儿患代谢性肝脏疾病的风险增加。我们对早产仔猪的初步研究表明，与肠内营养相比，富含植物甾醇和n-6脂肪酸（FA）的TPN可引起肝脏胆汁淤积、脂肪变性和炎症。TPN还能抑制血浆FGF19， FGF19是一种法脂类X受体（FXR）的产物，用FXR激动剂治疗TPN喂养的仔猪可逆转胆汁淤积。我们的主要假设是，肠外脂质营养缺乏植物甾醇，富含n-3和n-6 FA，可以通过激活FXR来预防早产TPN喂养仔猪与TPN相关的肝脏胆汁淤积和脂肪变性。AIM 1将测试不含植物甾醇的肠外脂质营养是否能预防独立于脂质负荷的tpn喂养的早产猪的肝脏代谢功能障碍。我们将使用体内代谢（13c -胆汁酸周转和13c -棕榈酸氧化动力学）和肝脏转录组学和代谢组学方法系统地量化肝脏胆汁酸和脂质代谢的代谢途径。RNAseq分析和代谢组学分析将用于鉴定潜在的新型肝脏基因和基因网络的差异表达。目的2将测试肠道外大豆脂质乳剂中的植物甾醇是否通过拮抗FXR受体功能诱导胆汁淤积和代谢性肝病。我们将测量13c -胆汁酸转换动力学、血清生化指标、肝脏组织病理学、FXR和FXR靶基因的组织表达，特别是参与胆汁酸代谢的CYP7A1。我们将使用肝细胞来测量FXR活性的表达，并使用单个植物甾醇以及FXR的激动剂和拮抗剂建立分子机制的特异性。AIM 3将测试天然和新型FXR选择性胆汁酸刺激肠道FGF19分泌是否通过FXR和CYP7A1信号的反馈调节来预防tpn诱导的胆汁淤积。我们将测量13c -胆汁酸转换动力学、血清标志物、肝脏组织病理学以及FXR、FGF19、CYP7A1和胆汁酸代谢相关靶基因的组织表达。我们将使用仔猪肝细胞培养物来检测FGF19、植物甾醇和不同脂质乳存在下FXR靶基因mRNA表达和FGF受体-4信号的表达。这些研究将在临床相关的新生儿动物模型中测试新的机制，以确定肠外脂质营养中的植物甾醇是否会对肝脏代谢功能和疾病产生不利影响。这些在早产儿猪身上的研究具有高度的转译性，并将在婴儿肝脏疾病的营养支持和预防方面带来新的临床实践。