D processes involved in lipid and PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/26748734 glucose metabolism in WT-PCLS and

D 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. PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28495172 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).(Continued on next page)* Correspondence: eszalow@gmail.com 1 RIKILT – Institute of Food Safety/Wageningen UR, Akkermaalsbos 2, P.O. Box 2306700 AE Wageningen, The Netherlands 3 RIKILT-Institute of Food Safety/Wageningen UR, Akkermaalsbos 2, 6708 WB Wageningen, The Netherlands Full list of author information is available at the end of the article?2015 Szalowska et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Szalowska et al. BMC Genomics (2015) 16:Page 2 of(Continued from previous page)Conclusions: Although FXR governs energy metabolism, no major differences in response Gepotidacin 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. Keywords: Farnesoid X receptor (FXR), Precision cut liver slices (PCLS), Cyclosporine A, Hepatotoxicity, Mitochondrial functions, Inflammation, Peroxisome proliferator-activated receptor (PPAR ), TranscriptomicsBackground Farnesoid X receptor (Fxr) is highly expressed in liver, intestine, kidney, adrenal glands and has a lower expression in white adipose tissue, pancreas, heart, and stomach [1]. Upon the discovery that bile acids (BA) are endogenous FXR agonists with chonedoexy cholic acid (CDCA) being the most potent FXR agonist, the primary functions of FXR were attributed to the maintenance of BA homeostasis [2]. FXR, upon activation by binding of a ligand, dimerizes either as a homodimer or as an heterodimer with another member of the nuclear receptor superfamily, retinoid X receptor (RXR), and binds to FXR response elements (FXRE) in the promoter region of its target genes to drive transcription [2]. 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). In addition, FXR can inhibit the expression of some of its target genes, including cholesterol-7hydroxylase (Cyp7a1), b.

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