Expression of bile acid synthesis and detoxification enzymes and the alternative bile acid efflux pump MRP4 in patients with primary biliary cirrhosis.
BACKGROUND
Bile acid synthesis, transport and metabolism are markedly altered in experimental cholestasis. Whether such coordinated regulation exists in human cholestatic diseases is unclear. We therefore investigated expression of genes for bile acid synthesis, detoxification and alternative basolateral export and regulatory nuclear factors in primary biliary cirrhosis (PBC).


METHODS
Hepatic CYP7A1, CYP27A1, CYP8B1 (bile acid synthesis), CYP3A4 (hydroxylation), SULT2A1 (sulphation), UGT2B4/2B7 (glucuronidation), MRP4 (basolateral export), farnesoid X receptor (FXR), retinoid X receptor (RXR), short heterodimer partner (SHP), hepatocyte nuclear factor 1alpha (HNF1alpha) and HNF4alpha expression was determined in 11 patients with late-stage PBC and this was compared with non-cholestatic controls.


RESULTS
CYP7A1 mRNA was repressed in PBC to 10-20% of controls, while CYP27 and CYP8B1 mRNA remained unchanged. SULT2A1, UGT2B4/2B7 and CYP3A4 mRNA levels were unaltered or only mildly reduced in PBC. MRP4 protein levels were induced three-fold in PBC, whereas mRNA levels remained unchanged. Expression levels of FXR, RXR, SHP, PXR, CAR, HNF1alpha and HNF4alpha were moderately reduced in PBC without reaching statistical significance.


CONCLUSIONS
Repression of bile acid synthesis and induction of basolateral bile acid export may represent adaptive mechanisms to limit bile acid burden in chronic cholestasis. As these changes do not sufficiently counteract cholestatic liver damage, future therapeutic strategies should aim at stimulation of bile acid detoxification pathways.
Zollner
Gernot
G
Laboratory of Experimental and Molecular Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
Wagner
Martin
M
Fickert
Peter
P
Silbert
Dagmar
D
Gumhold
Judith
J
Zatloukal
Kurt
K
Denk
Helmut
H
Trauner
Michael
M
D001647:Bile Acids and Salts / Q000378:metabolism*; D016022:Case-Control Studies; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis* / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D014453:Glucuronosyltransferase / Q000032:analysis* / Q000235:genetics; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008105:Liver Cirrhosis, Biliary / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000032:analysis* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis / Q000235:genetics; D012720:Severity of Illness Index; D015238:Sulfotransferases / Q000032:analysis* / Q000235:genetics; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics
D001647:Bile Acids and Salts; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D015238:Sulfotransferases; D014157:Transcription Factors; C073492:ABCC4 protein, human