Cyclosporin A induced toxicity in mouse liver slices is only slightly aggravated by Fxr-deficiency and co-occurs with upregulation of pro-inflammatory genes and downregulation of genes involved in mitochondrial functions

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.

Rat precision-cut liver slices predict drug-induced cholestatic injury

“…For example, a given drug can directly disrupt Fxr function or can influence its expression indirectly by triggering inflammatory and cytotoxic processes in the liver (Rodrigues et al 2014 ; Szalowska et al 2013 ). Various cholestatic drugs, including CP and CS, have been shown to cause ER stress, oxidative stress, apoptosis, trigger inflammatory responses and influence β-oxidation in the liver (Anthérieu et al 2013 ; Szalowska et al 2015 ; Vatakuti et al 2016 ). These pathological processes, in turn, can lead to the downregulation of Fxr , as well as other nuclear receptors (Szalowska et al 2013 ).…”

Role of farnesoid X receptor in cholestasis

“…Interestingly, cyclosporin Ainduced toxicity in mouse liver slices is only slightly aggravated by FXR deficiency, but the proinflammatory genes and those involved in mitochondrial functions are induced and downregulated, respectively. 56 In addition, FXR activation may also limit hepatic Journal of Digestive Diseases 2016; 17; 501-509 FXR and cholestasis inflammation by inhibiting the NF-κB-mediated inflammatory response, 40 while restricting fibrosis through the modulation of hepatic stellate cells. 57 FXR-deficient mice manifest with activated NF-κB and contribute to the development of alcoholic hepatitis.…”

“…Thus, FXR can regulate STAT3 and SOCS3 in an animal model of bile acid accumulation, which may partially contribute to the carcinogenesis of cholestasis. Interestingly, cyclosporin A‐induced toxicity in mouse liver slices is only slightly aggravated by FXR deficiency, but the proinflammatory genes and those involved in mitochondrial functions are induced and downregulated, respectively . In addition, FXR activation may also limit hepatic inflammation by inhibiting the NF‐κB‐mediated inflammatory response, while restricting fibrosis through the modulation of hepatic stellate cells .…”

Mitochondrial regulatory mechanisms in spinal cord injury: A narrative review

“…Owing to the reduction in ATP production, a large amount of heat is generated during the uncoupling process, causing hyperthermia, denaturation, and inactivation of various enzymes, which cannot meet normal life activities, resulting in cell death and organ failure. [93][94][95][96][97]…”