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


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.
Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, 70-111 Szczecin, Poland.
Ewa
E
Wunsch
Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland.
Marta
M
Klak
Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland.
Urszula
U
Wasik
Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland.
Malgorzata
M
Milkiewicz
Department of Medical Biology, Pomeranian Medical University, 70-111 Szczecin, Poland.
Malgorzata
M
Blatkiewicz
Department of Pathology, Pomeranian Medical University, 71-252 Szczecin, Poland.
Elzbieta
E
Urasinska
Laboratory of Molecular Pharmacology, CHU Québec and Faculty of Pharmacy, Laval University, Québec, QC, Canada.
Olivier
O
Barbier
Department of Gastroenterology, Pomeranian Medical University, 71-252 Szczecin, Poland.
Dariusz
D
Bielicki
Liver Sciences, Division of Liver Transplantation and Mucosal Biology, King's College London School of Medicine, Denmark Hill Campus, London SE5 9RS, UK ; Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa 41110, Greece.
Dimitrios P
DP
Bogdanos
Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, University of Birmingham, Birmingham B15 2TT, UK.
Elwyn
E
Elias
Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, 70-111 Szczecin, Poland ; Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 02-097 Warsaw, Poland.
Piotr
P
Milkiewicz
D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D015209:Cholangitis, Sclerosing / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D015238:Sulfotransferases / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
C526012:MIRN378 microRNA, human; D035683:MicroRNAs; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D015238:Sulfotransferases; C028152:alcohol sulfotransferase