Z Gastroenterol 2009; 47 - P2_25
DOI: 10.1055/s-0029-1191836

Regulation of nuclear receptors in non-alcoholic fatty liver disease: insights from ob/ob-mice

IV Martin 1, A Minkenberg 1, S Strauch 1, A Geier 2
  • 1Medizinische Klinik III, Universitätsklinikum Aachen, RWTH Aachen
  • 2Abteilung Gastroenterologie und Hepatologie, Universität Zürich, Schweiz

Introduction:

Non-alcoholic fatty liver diseases (NAFLD) affects ≤25% of the general population. Several nuclear receptors (NR) have been implied in the progression of NAFLD, e.g. through the regulation of FAS by Lrh-1, LXR and FXR and induction of PPARγ which is activated by PXR and influences Srebp-1c expression. KO-mice-studies assigned FXR a protective role in fatty liver development whereas the absence of SHP ameliorates fatty liver, intriguingly. Here we investigated NR regulation in NAFLD as a prerequisite for further therapeutic strategies in the ob/ob mouse-model.

Methods:

8 week-old male ob/ob-mice and controls were fed standard chow ad libitum for 6 weeks and liver mRNA, microsomes & nuclear protein was prepared. mRNA and protein expression was analyzed by real-time RT-PCR and Western Blotting. Binding activity of FXR to the IR-1 element was examined by EMSA.

Results:

Oatp1 and Oatp2 expression decrease dramatically in ob/ob-mice (mRNA: 2% & 55%, protein: ˜60%), while Oatp4 is elevated (mRNA 188%) and Ntcp remains unchanged. Mrp3 and Mrp4 are strongly increased to 300% and 5–10-fold (protein and mRNA), respectively. Bsep- and Mrp2-mRNAs are upregulated to ca. 200% while the respective proteins are decreased to ˜60%. PPARγ and Srebp-1c mRNA are drastically induced 7- and 60-fold. PXR-, LXR- and FXR-expression is increased between 1,5- and 5-fold as is the expression of VDR and RARα. Expression of SHP and Lrh-1 remained unchanged. Binding activity of FXR to the IR1-element is increased ˜2-fold in obese mice.

Conclusions:

Increased FXR-expression and DNA binding activity due to reduced bile acid export represents a central event in NAFLD in mice. Together with other activated NR such as PXR SHP-independent effects of FXR might be involved in a cross-talk between BA-signalling and the induction of their adipogenic target genes. However, the distinct role of FXR signals in the progression of fatty liver disease needs to be clarified in more detail.