title: Glucagon-Like Peptide-2 Alters Bile Acid Metabolism in Parenteral Nutrition--Associated Liver Disease.
abstract: 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.
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: David W
authors.initials: DW
authors.lastname: Lim
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada Department of Surgery, Hospital for Sick Children & University of Toronto, Toronto, Ontario, Canada.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Wales
authors.affiliation: Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Si
authors.initials: S
authors.lastname: Mi
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jason Y K
authors.initials: JY
authors.lastname: Yap
authors.affiliation: Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Curtis
authors.affiliation: Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Diana R
authors.initials: DR
authors.lastname: Mager
authors.affiliation: Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Vera C
authors.initials: VC
authors.lastname: Mazurak
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Wizzard
authors.affiliation: Department of Surgery, University of Calgary, Calgary, Alberta, Canada.
authors.forename: David L
authors.initials: DL
authors.lastname: Sigalet
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada Justine.turner@albertahealthservices.ca.
authors.forename: Justine M
authors.initials: JM
authors.lastname: Turner
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001647:Bile Acids and Salts / Q000378:metabolism*; D002779:Cholestasis / Q000150:complications / Q000188:drug therapy; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D053767:Glucagon-Like Peptide 2 / Q000494:pharmacology*; D008095:Lithocholic Acid / Q000378:metabolism; D008107:Liver Diseases / Q000150:complications / Q000188:drug therapy*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D010288:Parenteral Nutrition / Q000009:adverse effects*; D013552:Swine; D053719:Tandem Mass Spectrometry; D059467:Transcriptome
chemical_list: D001647:Bile Acids and Salts; D002790:Cholesterol 7-alpha-Hydroxylase; D053767:Glucagon-Like Peptide 2; D008095:Lithocholic Acid; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C114462:multidrug resistance-associated protein 3
keywords: bile acid; cholestasis; glucagon-like peptide-2; neonate; parenteral nutrition; parenteral nutrition–associated liver disease