title: Glutamine attenuates obstructive cholestasis in rats via farnesoid X receptor-mediated regulation of Bsep and Mrp2.
abstract: To investigate the protective effect of glutamine (Gln) against obstructive cholestasis in association with farnesoid X receptor (FXR) activation, an obstructive cholestasis model was established in male Sprague-Dawley rats by bile duct ligation (BDL). Serum biomarkers and hematoxylin plus eosin staining were used to identify the degree of hepatic injury in the rats with obstructive cholestasis after Gln treatment. Immunohistochemistry, real-time PCR, Western blot, cultured primary rat hepatocytes with FXR knockdown, and dual-luciferase reporter assay were performed to elucidate the mechanisms underlying Gln hepatoprotection. We found that Gln treatment protected against obstructive cholestasis induced by BDL through reducing hepatocyte injury. Upregulation of the hepatic efflux transporters small heterodimer partner (Shp), bile salt export pump (Bsep), and multidrug resistance-associated protein 2 (Mrp2), and inhibition of the hepatic uptake transporter Na+/taurocholate cotransporting polypeptide (Ntcp) and the bile acid synthesis enzyme cholesterol 7α-hydroxylase (Cyp7a1) expression were observed in rats with BDL treated with Gln in vivo. Furthermore, the regulatory effect of Gln on Bsep and Mrp2 expression was abrogated after FXR knockdown in rat primary cultured hepatocytes. Luciferase assay HepG2 cells also illustrated FXR was a direct target for Gln treatment. In conclusion, the regulation of Bsep and Mrp2 expression mediated by FXR might be an important mechanism for Gln against obstructive cholestasis.
authors.affiliation: a Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
authors.forename: Bingli
authors.initials: B
authors.lastname: Liu
authors.affiliation: a Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Li
authors.affiliation: a Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Ji
authors.affiliation: a Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Lu
authors.affiliation: a Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: b Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
authors.forename: Yakun
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D002779:Cholestasis / Q000378:metabolism* / Q000473:pathology; D002790:Cholesterol 7-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D005973:Glutamine / Q000009:adverse effects / Q000494:pharmacology*; D022781:Hepatocytes / Q000378:metabolism; D008111:Liver Function Tests; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors; D061251:Primary Cell Culture; D020011:Protective Agents / Q000009:adverse effects / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D027981:Symporters / Q000037:antagonists & inhibitors; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D002790:Cholesterol 7-alpha-Hydroxylase; D005973:Glutamine; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D020011:Protective Agents; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D027981:Symporters; D000099150:Receptor, Farnesoid X-Activated; C490548:Abcb11 protein, rat; C099713:nuclear receptor subfamily 0, group B, member 2; C071908:sodium-bile acid cotransporter
keywords: Bsep; FXR; Mrp2; acide biliaire; bile acid; cholestase obstructive; glutamine; obstructive cholestasis