高血糖素样肽-2改变肠外营养相关肝病的胆汁酸代谢

　　背景：我们旨在研究前期发现外源性胰高血糖素样肽-2（GLP-2）治疗可以改善肠外营养相关肝病（PNALD）幼猪模型胆汁淤积的潜在机制。

　　方法：通过对幼猪进行17天肠外营养（PN），以生理盐水作为对照（PN/Saline，n=8），另一组给予11nmol/kg/d的GLP-2（PN/GLP-2，n=7）。在剖腹手术中收集胆汁和肝脏标本。通过实时定量PCR检测肝脏中胆汁酸合成酶，调节酶，转运酶的相对基因表达水平。通过串联质谱技术确定胆汁中胆汁酸的成分。以单因素方差分析（ANOVA）或Kruskal-Wallis ANOVA分析数据。

　　结果：与生理盐水对照组相比，GLP-2增加了胆汁酸排出基因的表达：多药耐药相关蛋白（MRP）2（P=0.002）和3（MRP3）（P=0.037）。GLP-2增加了法尼酯X受体（FXR）（P＜0.001）和CYP7A1（细胞色素P450，家族7，亚家族A，多肽1）（P=0.03）的表达.GLP-2的治疗有助于降低猪胆酸和有毒胆石酸赘生物的浓度（P＜0.01）。GLP-2的治疗增加了胆汁酸的量。

　　结论：GLP-2的治疗与肝脏胆汁酸代谢相关基因表达的改变有关。转录结果提示转录水平的机制是通过调节胆汁酸合成和增加胆汁酸的排出实现的。胆汁酸的差异进一步支持了GLP-2在治疗PNALD中的有益作用。

JPEN J Parenter Enteral Nutr. 2016;40(1):22-35.

Glucagon-Like Peptide-2 Alters Bile Acid Metabolism in Parenteral Nutrition-Associated Liver Disease.

Lim DW, Wales PW, Mi S, Yap JY, Curtis JM, Mager DR, Mazurak VC, Wizzard PR, Sigalet DL, Turner JM.

University of Alberta, Edmonton, Alberta, Canada; Hospital for Sick Children & University of Toronto, Toronto, Ontario, Canada; University of Calgary, Calgary, Alberta, Canada.

BACKGROUND: We aim to study the mechanisms underlying our previous finding that exogenous glucagon-like peptide-2 (GLP-2) treatment in a preclinical model of neonatal parenteral nutrition-associated liver disease (PNALD) improves cholestasis.

METHODS: Neonatal piglets received 17 days of parenteral nutrition (PN) therapy and either saline control (PN/Saline n = 8) or GLP-2 treatment at 11 nmol/kg/d (PN/GLP-2, n = 7). At terminal laparotomy, bile and liver samples were collected. The relative gene expression of enzymes involved in bile acid synthesis, regulation, and transport was measured in liver by reverse-transcriptase quantitative polymerase chain reaction. Bile acid composition in bile was determined using tandem mass spectrometry. Data were analyzed using 1-way analysis of variance (ANOVA) or Kruskal-Wallis ANOVA.

RESULTS: GLP-2 increased the expression of bile acid export genes: multidrug resistance-associated proteins 2 (MRP2) (P = .002) and 3 (MRP3) (P = .037) over saline control. GLP-2 increased expression of Farnesoid X receptor (FXR) (P < .001) and CYP7A1 (cytochrome P450, family 7, subfamily A, polypeptide 1) (P = .03). GLP-2 treatment was associated with decreased concentrations of taurohyocholic acid and conjugates of toxic lithocholic acid (P < .01). GLP-2 treatment increased the liver bile acid content.

CONCLUSIONS: GLP-2 treatment was associated with alterations in the hepatic expression of genes involved in bile acid metabolism. The transcriptomic results indicate the mechanisms at the transcriptional level acting to regulate bile acid synthesis and increase bile acid export. Differences in bile acid profiles further support a beneficial role for GLP-2 therapy in PNALD.

KEYWORDS: bile acid; cholestasis; glucagon-like peptide-2; neonate; parenteral nutrition; parenteral nutrition–associated liver disease

PMID: 26220199

DOI: 10.1177/0148607115595596