Get access

Expression of bile acid synthesis and detoxification enzymes and the alternative bile acid efflux pump MRP4 in patients with primary biliary cirrhosis


Michael Trauner, Professor of Medicine and Molecular Hepatology, Laboratory of Experimental and Molecular Hepatology, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Auenbruggerplatz 15, A-8036 Graz, Austria
Tel: ++43 316 385 4388
Fax: ++43 316 385 7560


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).

Material/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 1α (HNF1α) and HNF4α 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, HNF1α and HNF4α were moderately reduced in PBC without reaching statistical significance.

Summary/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.

Get access to the full text of this article