FXR cistrome in mouse liver
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE87866 | GEO | 2016/10/13
SECONDARY ACCESSION(S): PRJNA347972
REPOSITORIES: GEO
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Project description:Autophagy is an evolutionally conserved catabolic process that recycles nutrients upon starvation and maintains cellular energy homeostasis1-3. Its acute regulation by nutrient sensing signaling pathways is well described, but its longer-term transcriptional regulation is not. The nuclear receptors PPARα and FXR are activated in the fasted or fed liver, respectively4,5. Here we show that both regulate hepatic autophagy. Pharmacologic activation of PPARα reverses the normal suppression of autophagy in the fed state, inducing autophagic lipid degradation, or lipophagy. This response is lost in PPARα knockout (PPARα-/-) mice, which are partially defective in the induction of autophagy by fasting. Pharmacologic activation of the bile acid receptor FXR strongly suppresses the induction of autophagy in the fasting state, and this response is absent in FXR knockout (FXR-/-) mice, which show a partial defect in suppression of hepatic autophagy in the fed state. PPARα and FXR compete for binding to shared sites in autophagic gene promoters, with opposite transcriptional outputs. These results reveal complementary, interlocking mechanisms for regulation of autophagy by nutrient status. Mouse liver PPARα cistromes in fed 8-week-old male WT or PPARα KO mice treated with or without its synthetic agonist ligand GW7647twice a day were generated by deep sequencing in quadruplicate using illumina
2014-09-27 | E-GEOD-61817 | biostudies-arrayexpress
Project description:Autophagy is an evolutionally conserved catabolic process that recycles nutrients upon starvation and maintains cellular energy homeostasis1-3. Its acute regulation by nutrient sensing signaling pathways is well described, but its longer-term transcriptional regulation is not. The nuclear receptors PPARα and FXR are activated in the fasted or fed liver, respectively4,5. Here we show that both regulate hepatic autophagy. Pharmacologic activation of PPARα reverses the normal suppression of autophagy in the fed state, inducing autophagic lipid degradation, or lipophagy. This response is lost in PPARα knockout (PPARα-/-) mice, which are partially defective in the induction of autophagy by fasting. Pharmacologic activation of the bile acid receptor FXR strongly suppresses the induction of autophagy in the fasting state, and this response is absent in FXR knockout (FXR-/-) mice, which show a partial defect in suppression of hepatic autophagy in the fed state. PPARα and FXR compete for binding to shared sites in autophagic gene promoters, with opposite transcriptional outputs. These results reveal complementary, interlocking mechanisms for regulation of autophagy by nutrient status.
2014-09-27 | GSE61817 | GEO
Project description:The Farnesoid-X-Receptor (FXR) is a nuclear receptor (NR) known to obligately heterodimerize with Retinoid-X-Receptor (RXR). FXR is expressed as four isoforms (α1-α4) that drive transcription from IR-1 (inverted repeat-1) DNA motifs. More recently, FXR isoforms α2/α4 were found to activate transcription predominantly from non-canonical ER-2 (everted repeat-2) DNA motifs, mediating most metabolic effects of general FXR activation.Here, we explored whether co-occupancy of FXR and RXR in the mouse liver has an influence on DNA motif binding preference. We found RXR acts as a molecular switch, promoting FXRα2 activation from IR-1 instead of ER-2 motifs. Our results showcase FXR as the first NR with RXR-dependent and independent modes of activation, highlighting a potential new layer of complexity for other RXR-heterodimerizing NRs.
2024-03-20 | GSE261901 | GEO
Project description:The farnesoid X receptor (FXR) is a nuclear receptor activated by bile acids and regulates bile acid metabolism, glucose and cholesterol homeostasis. From mouse studies we know that the novel FXR agonist obeticholic acid (OCA) regulates expression of many genes in the liver, but there is currently no data on the effects of OCA on human liver gene expression. This is especially relevant since the novel FXR agonist OCA is currently tested in clinical trials for the treatment of several diseases, such as nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD) and Type 2 Diabetes. In this study we investigate the effect of OCA treatment on gene expression profiles and localization of FXR to the genome in relevant liver samples. ChIP-Seq for FXR in Liver tissue from 2 male mice treated with OCA/INT-747 (10mg/kg/day) and 2 male mice treated with vehicle (1% methyl cellulose).
2016-01-27 | E-GEOD-73624 | biostudies-arrayexpress
Project description:The farnesoid X receptor (FXR) is a nuclear receptor activated by bile acids that regulates metabolic processes. FXR is expressed as four isoforms (α1-4), and their relative abundance is specific to tissue and bio-energetic conditions (Correia JC et al. 2015). Depending on the FXR isoform expressed, there is a degree of selectivity in target-genes activation. In this dataset, we defined FXR-isoforms selective effects on transcription in mouse liver organoids after treatment with the FXR agonist Obeticholic acid(OCA). By linking the DNA binding profiles of the FXR isoforms with their transcriptional output, we concluded that differential DNA binding plays a defining role in FXR-isoform target gene selectivity.
2020-07-27 | GSE133734 | GEO
Project description:The farnesoid X receptor (FXR) is a nuclear receptor activated by bile acids that regulates metabolic processes. FXR is expressed as four isoforms (α1-4), and their relative abundance is specific to tissue and bio-energetic conditions (Correia JC et al. 2015). Depending on the FXR isoform expressed, there is a degree of selectivity in target-genes activation. However, there is currently no data on how isoform-linked target selectivity is achieved. In this study we investigate the DNA binding profile of FXR isoforms on mouse liver organoids treated briefly with the FXR agonist obeticholic acid (OCA). From this analysis we concluded that FXR isoforms α2 and α4 binds to additional DNA regions, enriched for a specific discriminating binding motif. This binding led to isoform-selective gene regulation. Therefore, DNA binding selectivity therefore plays a defining role in FXR isoform-specific effects.
2020-07-27 | GSE133700 | GEO
Project description:Background: The bile acid-activated farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, glucose and cholesterol homeostasis. Obeticholic acid (OCA; also known as INT-747 or 6α-ethyl-chenodeoxycholic acid), a promising drug for the treatment of non-alcoholic steatohepatitis (NASH) and type 2 diabetes, activates FXR. Mouse studies demonstrated that FXR activation by OCA (INT-747) alters hepatic expression of many genes. However, no data are available on the effects of OCA in human liver. Here, we generated gene expression profiles in human precision-cut liver slices (hPCLS) after treatment with OCA. Methods: hPCLS were incubated with OCA for 24 h. WT or FXR -/- mice received OCA or vehicle by oral gavage for 7 days. Results: Transcriptomic analysis showed that well-known FXR target genes, including NR0B2 (SHP), ABCB11 (BSEP), SLC51A (OSTα) and SLC51B (OSTβ) and ABCB4 (MDR3), are regulated by OCA in hPCLS. Ingenuity pathway analysis confirmed that 'FXR/RXR activation' is the most significantly changed pathway upon OCA treatment. Comparison of gene expression profiles in hPCLS and mouse livers identified 18 common potential FXR targets. ChIP-sequencing in mouse liver confirmed FXR binding to IR1 sequences of Akap13, Cgnl1, Dyrk3, Pdia5, PPP1R3B and Tbx6. Conclusions: Our study shows that hPCLS respond to OCA treatment by upregulating well-known FXR target genes, demonstrating its suitability to study FXR-mediated gene regulation. We identified 6 novel bona-fide FXR target genes in both mouse and human liver. Finally, we discuss a possible explanation for changes in HDL/LDL observed in NASH and primary biliary cirrhosis patients treated with OCA based on the genomic expression profile in hPCLS.
2016-01-27 | GSE76162 | GEO
Project description:The inter-organ cross talk between liver and intestine has been focus of intense research. Key in this cross-talk are bile acids, which are secreted from the liver into the intestine and, via the enterohepatic circulation, reach back to the liver. Important new insights have been gained in the Farnesoid X receptor (Fxr)-mediated communication from intestine-to-liver in health and disease. However, liver-to-intestine communication and the role of bile acids and FXR in this cross talk remain elusive. Here, we analyse Fxr-mediated liver-to-gut communication, and its consequences in the colon. Mice in which Fxr was selectively ablated in intestine (Fxr-intKO), the liver (Fxr-livKO), or in the full body (Fxr-totKO) were engineered. The effects on colonic gene expression (RNA sequencing), on the microbiome (16S rRNA Gene Sequencing) and on mucus barrier were analyzed. Compared to Fxr-intKO and Fxr-totKO mice, more genes were differentially expressed in the colons of Fxr-livKO mice relative to control mice (731, 1824 and 3272 respectively), suggestive of a strong role of hepatic Fxr in liver-to-gut communication. The colons of Fxr-livKO showed increased expression of anti-microbial genes, such as Regenerating islet-derived 3 beta and gamma (Reg3β and Reg3γ), Toll-like receptors (Tlrs), inflammasome related genes and differential expression of genes belonging to the ‘Mucin-type O-glycan biosynthesis’ pathway. Compared to control mice, Fxr-livKO mice have decreased levels of the predicted mucin degrading bacterium Turicibacter and a concomitant increase in the thickness of the inner sterile mucus layer. In conclusion, ablation of Fxr in the liver has a major effect on colonic gene expression, the gut microbiome and on the permeability of the mucus layer. This stresses the importance of the Fxr-mediated liver-to-gut signaling.
2021-09-29 | GSE163157 | GEO
Project description:Mouse primary hepatocytes (MPH) prepared from C57Bl6 male adult mice were challenged with the FXR agonist GW4064 and used to prepare RNA which was then processed for analysis using MoGene-2_0-st Affymetrix microarrays according to standard procedures.
2017-03-30 | GSE87566 | GEO
Project description:Bile acid (BA) homeostasis is maintained through a feedback loop operated by the nuclear hormone receptors FXR and SHP. Here we show that contrary to the current models placing FXR upstream of SHP in a linear regulatory pathway, the phenotypic consequence of the combined loss of both receptors is much more severe than the relatively modest impact of the loss of either Fxr or Shp alone. This is highlighted by the dramatic elevation of hepatic and serum BA levels in the double knockout (DKO) mice as early as three weeks of age coupled with a commensurate increase in Cyp7A1 expression and alterations in BA homeostatic genes. In addition, we find several genes necessary for C21 steroid biosynthetic pathway as novel targets for FXR and SHP. The elevated BAs result in severe hepato-pathology but the DKO mice surprisingly do not develop complete liver failure and live for over a year. Their survival is accompanied by an adaptive proliferation of the resident liver progenitor cell population, known as oval cells. Overall, these data demonstrate that FXR and SHP function coordinately to maintain BA homeostasis, and identify DKO mice as a novel genetic model for juvenile cholestatic disorders and for oval cell activation. Liver samples collected from FXR-/-, SHP-/-, and FXR-/-/SHP-/- animals at 3 or 5 weeks were hybridized to Illumina mouse REF-8 v1.1 arrays in duplicate.
2010-12-10 | E-GEOD-20599 | biostudies-arrayexpress