Impaired Hepatic Adaptation to Chronic Cholestasis induced by Primary Sclerosing Cholangitis

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.