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.

Metabolomic Profiling of Portal Blood and Bile Reveals Metabolic Signatures of Primary Sclerosing Cholangitis

“…End-stage PSC and DC patients both demonstrate enrichment in conjugated forms of chenodeoxycholic acid in their portal serum. This is consistent with the reduction in microsomal sterol 12α-hydroxylase (CYP8B1) levels that have previously been observed in the setting of PSC cirrhosis [ 29 ]. Conversely, some secondary bile acids are decreased in both PSC and DC cohorts, suggesting a reduction in the microbial population capable of bile salt hydrolase and other secondary bile acid enzymatic activities.…”

“…Studies in nonalcoholic liver disease demonstrate that FFAs can disrupt short heterodimer partner (SHP)-induced FXR activation, leading to the upregulation of NTCP and CYP7A1, thereby permitting unregulated bile acid synthesis and subsequent hepatic injury [ 31 ]. In PSC, there is a lack of CYP7A1 suppression despite high levels of SHP and FXR gene expression, supporting the presence of dysregulated SHP signaling [ 29 ]; however, this may not be a generalizable feature of PSC, as very low levels of serum C4 (an indicator of CYP7A1 enzymatic activity) were detected in the advanced stages of PSC [ 32 ]. The elevated levels of FFAs may indicate possible defects in β-oxidation, which is also enabled by FXR as well as peroxisome proliferator-activated receptor-alpha (PPAR-α) [ 33 , 34 ].…”

Comparison of intestinal expression of the apical sodium‐dependent bile acid transporter between dogs with and without chronic inflammatory enteropathy

“…In most laboratory species, including the mouse, rat, and hamster, the distribution of ASBT in the intestine is limited to the terminal ileum. In humans, however, ASBT also is expressed in the duodenum and colon at both mRNA and protein levels. In our study, low mRNA levels of ASBT were observed in the proximal small intestine (ie, duodenum and jejunum), but ASBT protein was not detected in these segments.…”

Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities

“…Toxic effects of bile upon cholangiocytes [32,45], due to cholestasis, or primary or secondary changes in bile composition as part of disease processes in the bile ducts or colon [46][47][48][49][50], or impairment of protective means (e.g. the so-called ''bicarbonate umbrella'') [51], may contribute to biliary inflammatory and fibrotic processes.…”