Abstract
BackgroundThe transcription factor farnesoid X receptor (FXR) governs bile acid and energy homeostasis, is involved in inflammation, and has protective functions in the liver. In the present study we investigated the effect of Fxr deficiency in mouse precision cut liver slices (PCLS) exposed to a model hepatotoxicant cyclosporin A (CsA). It was anticipated that Fxr deficiency could aggravate toxicity of CsA in PCLS and pinpoint to novel genes/processes regulated by FXR.MethodsTo test this hypothesis, PCLS obtained from livers of wild type mice (WT-PCLS) and Fxr-knockout mice (FXRKO-PCLS) were treated with 40 μM CsA for 24 h and 48 h. ATP and histological assays were applied to assess the viability of PCLS. DNA microarrays combined with bioinformatics analysis were used to identify genes and processes that were affected by CsA in WT-PCLS and/or FXRKO-PCLS. In addition, WT-PCLS and FXRKO-PCLS were exposed to the endogenous FXR ligand chenodeoxycholic acid (CDCA) and subjected to q-PCR to determine whether subsets of known FXR-targets and the identified genes were regulated upon FXR activation in an FXR-dependent manner.ResultsNo difference in viability was observed between WT-PCLS and FXRKO-PCLS upon CsA treatment. Transcriptomics data analysis revealed that CsA significantly upregulated stress-response and inflammation and significantly downregulated processes involved in lipid and glucose metabolism in WT-PCLS and FXRKO-PCLS. However, only in FXRKO-PCLS, CsA upregulated additional pro-inflammatory genes and downregulated genes related to mitochondrial functions. Furthermore, only in WT-PCLS, CDCA upregulated a subset of known FXR-target genes as well as the regulator of inflammation and mitochondrial functions peroxisome proliferator- activated receptor delta (Ppar delta).ConclusionsAlthough FXR governs energy metabolism, no major differences in response to CsA could be observed between WT-PCLS and FXRKO-PCLS in regulation of processes involved in lipid and glucose metabolism. This finding indicates that CsA does not directly affect FXR functions in relation to the above mentioned processes. However, the more pronounced induction of pro-inflammatory genes and the downregulation of genes involved in mitochondrial functions only in FXRKO-PCLS suggest that FXR deficiency aggravates CsA-induced inflammation and impairs mitochondrial functions. Therefore, FXR can exert its hepatoprotective functions by controlling inflammation and mitochondrial functions, possibly involving an FXR-PPAR delta cross-talk.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-2054-7) contains supplementary material, which is available to authorized users.
Highlights
The transcription factor farnesoid X receptor (FXR) governs bile acid and energy homeostasis, is involved in inflammation, and has protective functions in the liver
FXR governs energy metabolism, no major differences in response to cyclosporin A (CsA) could be observed between wild type (WT)-precision cut liver slices (PCLS) and FXRKO-PCLS in regulation of processes involved in lipid and glucose metabolism
There was no statistically significant difference in the normalized ATP content between WT-PCLS and FXRKOPCLS treated with Dimethyl sulfoxide (DMSO) or CsA indicating that exposure of both types of slices to 40 μM CsA did not result in cytotoxicity (Fig. 1)
Summary
The transcription factor farnesoid X receptor (FXR) governs bile acid and energy homeostasis, is involved in inflammation, and has protective functions in the liver. FXR positively regulates the expression of several genes coding transporters and enzymes involved in BA homeostasis including bile salt export pump (BSEP), bile acid-CoA:amino acid N-acyltransferase (BAAT), or multidrug resistance protein 3 (MDR3). FXR can inhibit the expression of some of its target genes, including cholesterol-7αhydroxylase (Cyp7a1), by a mechanism referred to as trans-repression involving induction of other transcription factors, such as small heterodimer partner (Shp). In liver FXR upregulates its direct target gene Shp, which in turn inhibits expression of the liver receptor homolog (Lrh)-1, liver X receptor (Lxr), and hepatocyte nuclear factor 4 α (Hnf4α), all necessary for constitutive expression of Cyp7a1, coding a rate limiting enzyme in the synthesis of BA from cholesterol [3]
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