title: Impaired Hepatic Adaptation to Chronic Cholestasis induced by Primary Sclerosing Cholangitis.
abstract: Pathogenesis of primary sclerosing cholangitis (PSC) may involve impaired bile acid (BA) homeostasis. We analyzed expressions of factors mediating enterohepatic circulation of BA using ileal and colonic (ascending and sigmoid) biopsies obtained from patients with PSC with and without ulcerative colitis (UC) and explanted PSC livers. Two-fold increase of BA-activated farnesoid X receptor (FXR) protein levels were seen in ascending and sigmoid colon of PSC patients with correspondingly decreased apical sodium-dependent BA transporter (ASBT) gene expression. This was associated with increased OSTβ protein levels in each part of analyzed gut. An intestinal fibroblast growth factor (FGF19) protein expression was significantly enhanced in ascending colon. Despite increased hepatic nuclear receptors (FXR, CAR, SHP), and FGF19, neither CYP7A1 suppression nor CYP3A4 induction were observed. The lack of negative regulation of BA synthesis may be accountable for lower levels of cholesterol observed in PSC in comparison to primary biliary cholangitis (PBC). In conclusion, chronic cholestasis in PSC induces adaptive changes in expression of BA transporters and FXR in the intestine. However hepatic impairment of expected in chronic cholestasis downregulation of CYP7A1 and upregulation of CYP3A4 may promote BA-induced liver injury in PSC.
authors.affiliation: Department of Medical Biology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Milkiewicz
authors.affiliation: Department of Medical Biology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Klak
authors.affiliation: Department of Medical Biology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kempinska-Podhorodecka
authors.affiliation: Endoscopy Unit, Ministry of Internal Affairs Hospital, Szczecin, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Wiechowska-Kozlowska
authors.affiliation: Department of Pathology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Urasinska
authors.affiliation: Department of Medical Biology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Blatkiewicz
authors.affiliation: Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Wunsch
authors.affiliation: Liver and Hepatobiliary Unit, University of Birmingham, Birmingham, UK.
authors.forename: Elwyn
authors.initials: E
authors.lastname: Elias
authors.affiliation: Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland.|Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery of the Medical University of Warsaw, Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Milkiewicz
mesh_terms: D000328:Adult; D001647:Bile Acids and Salts / Q000378:metabolism*; D001706:Biopsy; D015209:Cholangitis, Sclerosing / Q000473:pathology*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D002908:Chronic Disease; D003106:Colon / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D055815:Young Adult; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002790:Cholesterol 7-alpha-Hydroxylase; D051544:Cytochrome P-450 CYP3A; D005346:Fibroblast Growth Factors; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C117476:FGF19 protein, human; C553219:CYP7A1 protein, human; C510163:CYP3A4 protein, human