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Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Zollner, G; Wagner, M; Fickert, P; Silbert, D; Gumhold, J; Zatloukal, K; Denk, H; Trauner, M.
Expression of bile acid synthesis and detoxification enzymes and the alternative bile acid efflux pump MRP4 in patients with primary biliary cirrhosis.
Liver Int. 2007; 27(7):920-929
Doi: 10.1111/j.1478-3231.2007.01506.x
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- Führende Autor*innen der Med Uni Graz
- Trauner Michael
- Zollner Gernot
- Co-Autor*innen der Med Uni Graz
- Denk Helmut
- Fickert Peter
- Silbert-Wagner Dagmar
- Sommer Judith
- Wagner Martin
- Zatloukal Kurt
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- Abstract:
- 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). 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. 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. 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Bile Acids and Salts - metabolism
- Case-Control Studies -
- Cytochrome P-450 Enzyme System - analysis Cytochrome P-450 Enzyme System - genetics
- Female -
- Gene Expression Regulation -
- Glucuronosyltransferase - analysis Glucuronosyltransferase - genetics
- Humans -
- Liver - enzymology Liver - metabolism
- Liver Cirrhosis, Biliary - enzymology Liver Cirrhosis, Biliary - genetics Liver Cirrhosis, Biliary - metabolism
- Male -
- Middle Aged -
- Multidrug Resistance-Associated Proteins - analysis Multidrug Resistance-Associated Proteins - genetics
- RNA, Messenger - metabolism
- Receptors, Cytoplasmic and Nuclear - analysis Receptors, Cytoplasmic and Nuclear - genetics
- Severity of Illness Index -
- Sulfotransferases - analysis Sulfotransferases - genetics
- Transcription Factors - analysis Transcription Factors - genetics
- Find related publications in this database (Keywords)
- bile acids
- cholestasis
- hepatocyte-enriched transcription factor
- nuclear receptors
- transport