Liver Expression of Sulphotransferase 2A1 Enzyme Is Impaired in Patients with Primary Sclerosing Cholangitis: Lack of the Response to Enhanced Expression of PXR

Abstract

Background/Aim. Sulphotransferase 2A1 (SULT2A1) exerts hepatoprotective effects. Transcription of SULT2A1 gene is induced by pregnane-X-receptor (PXR) and can be repressed by miR-378a-5p. We studied the PXR/SULT2A1 axis in chronic cholestatic conditions: primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). Materials/Methods. Western-blot/PCRs for SULT2A1/PXR were performed in PSC (n = 11), PBC (n = 19), and control liver tissues (n = 19). PXR and SULT2A1 mRNA was analyzed in intestinal tissues from 22 PSC patients. Genomic DNA was isolated from blood of PSC patients (n = 120) and an equal number of healthy volunteers. Liver miRNA expression was evaluated using Affymetrix-Gene-Chip miRNA4.0. Results. Increased PXR protein was observed in both PSC and PBC compared to controls and was accompanied by a significant increase of SULT2A1 in PBC but not in PSC. Decreased expression of SULT2A1 mRNA was also seen in ileum of patients with PSC. Unlike PBC, miRNA analysis in PSC has shown a substantial increase in liver miR-378a-5p. Conclusions. PSC is characterized by disease-specific impairment of SULT2A1 expression following PXR activation, a phenomenon which is not noted in PBC, and may account for the impaired hepatoprotection in PSC. miRNA analysis suggests that SULT2A1 expression in PSC may be regulated by miR-378a-5p, connoting its pathogenic role.

Impaired Hepatic Adaptation to Chronic Cholestasis induced by Primary Sclerosing Cholangitis

“…Despite the limitations, our present findings could be of value in further elucidation of the mechanisms involved in pathogenesis of chronic cholestatic conditions. PBC and PSC undeniably show important differences in terms of hepatic nuclear receptors, enzymes, and transporter expressions, as has been previously demonstrated by our group and others122936. The current results highlight the need for further investigations of the underlying processes leading to the lack of CYP7A1 suppression and the impaired CYP3A4 induction that were observed in PSC but not PBC.…”

“…Zollner and co-workers described unchanged mRNA expression of this detoxification enzyme in patients with PBC, which they explained based on the relatively low expressions of hepatic FXR, PXR, and CAR mRNA. However, in our present and prior studies, we found that the protein levels of these nuclear receptor were substantially enhanced in both PSC and PBC1223. The authors also suggested an alternative explanation based on the assumption that the NR-induced CYP3A4 expression is dependent on the disease stage, with CYP3A4 induction present only in the early disease stages.…”

“…We did not observe the enhanced expression of hepatic CYP3A4 in PSC patients neither on mRNA nor protein level (Fig. 6c), whereas the expression of nuclear receptors that induce CYP3A4 transcription, including PXR12 and CAR were substantially increased both on mRNA and protein levels. (3.09 ± 0,3 vs. 1.4 ± 0.3, and 7.1 ± 4 vs. 1.03 ± 0.2, P = <0.001 and P  = 0.03 vs. controls, respectively Fig.…”

“…. Six histological features were evaluated as previously described12. Due to the limited available biopsy material, distinct investigations were performed based on mRNA analysis.…”

Diagnostic and therapeutic potentials of microRNAs in cholangiopathies

“…This publication noted increased hepatic expression of miR-378a-5p in PSC patients compared with healthy controls [47]. This paper further identified sulphotransferase 2A1 (SULT2A1), generally suggested to be a hepatoprotective protein, as a target of miR-378a-5p.…”