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The nuclear Bile Acid Receptor FXR is a PKA- and FOXA2- sensitive Activator of Fasting Hepatic Gluconeogenesis

ABSTRACT: The nuclear Bile Acid Receptor FXR is a PKA- and FOXA2- sensitive Activator of Fasting Hepatic Gluconeogenesis

PROVIDER: PRJNA453136 | ENA |

REPOSITORIES: ENA

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The nuclear Bile Acid Receptor FXR is a PKA- and FOXA2- sensitive Activator of Fasting Hepatic Gluconeogenesis [modulated FOXA2/FXR]

Project description:Identified genes deregulated in mouse primary hepatocytes after modulation of expression/activity of FOXA2 and FXR in glucagon or insulin state

2018-08-16 | GSE113549 | GEO

The nuclear Bile Acid Receptor FXR is a PKA- and FOXA2- sensitive Activator of Fasting Hepatic Gluconeogenesis [modulated FOXA2/FXR]

Project description:The nuclear Bile Acid Receptor FXR is a PKA- and FOXA2- sensitive Activator of Fasting Hepatic Gluconeogenesis [modulated FOXA2/FXR]

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The nuclear Bile Acid Receptor FXR is a PKA- and FOXA2- sensitive Activator of Fasting Hepatic Gluconeogenesis [glucacon/GW4064]

Project description:The nuclear Bile Acid Receptor FXR is a PKA- and FOXA2- sensitive Activator of Fasting Hepatic Gluconeogenesis [glucacon/GW4064]

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The nuclear Bile Acid Receptor FXR is a PKA- and FOXA2- sensitive Activator of Fasting Hepatic Gluconeogenesis

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-08-16 | GSE113575 | GEO

Pioneer factor Foxa2 mediates chromatin conformation changes in ligand-dependent activation of nuclear receptor FXR

Project description:Activation of nuclear receptors, a family of ligand-dependent transcription factors, is used extensively in development of drug targets. We have previously shown that pioneer factor Foxa2 opens chromatin for binding of nuclear receptors FXR and LXRα during acute ligand activation. FXR is activated by bile acids and deletion of Foxa2 in the liver results in intrahepatic cholestasis. We hypothesized that Foxa2 also enables chromatin conformational changes during ligand activation. We performed Foxa2 HiChIP to assess Foxa2-dependent long-range interactions in mouse livers treated with either vehicle control or FXR agonist GW4064. HiChIP contact analysis shows that global chromatin interactions are dramatically increased during FXR activation. Ligand-treated livers exhibit extensive redistribution of topological associated domains (TAD) and substantial increase in Foxa2-anchored loops, suggesting Foxa2 is involved in dynamic chromatin conformational changes. We demonstrate that chromatin conformation, including genome-wide interactions, TADs, intra-chromosomal and inter-chromosomal Foxa2-anchored loops, drastically changes upon addition of FXR agonist. Hence, we determine a novel role for Foxa2 in enabling these conformational changes, extending its function in bile acid metabolism.

2023-10-16 | GSE229049 | GEO

The nuclear Bile Acid Receptor FXR is a PKA- and FOXA2- sensitive Activator of Fasting Hepatic Gluconeogenesis [glucacon/GW4064]

Project description:Identified genes deregulated in mouse primary hepatocytes after glucagon and /or GW4064 treatment

2018-08-16 | GSE113526 | GEO

Pioneer factor Foxa2 enables ligand-dependent activation of type II nuclear receptors FXR and LXRa

Project description:Type II nuclear hormone receptors, such as FXR, LXR, and PPAR, which function in glucose and lipid metabolism and serve as drug targets for metabolic diseases, are permanently positioned in the nucleus regardless of the ligand status. Ligand activation of these receptors is thought to occur by co-repressor/co-activator exchange, followed by initiation of transcription. However, recent genome-wide location analysis showed that LXRα and PPARα binding in the liver is largely ligand-dependent. We hypothesized that pioneer factor Foxa2 evicts nucleosomes to enable ligand-dependent receptor binding. We show that chromatin accessibility, FXR binding and LXRα occupancy, and ligand-responsive activation of gene expression by FXR and LXRα require Foxa2. Unexpectedly, Foxa2 occupancy is drastically increased when either receptor, FXR or LXRα, is bound by an agonist. In addition, co-immunoprecipitation experiments demonstrate that Foxa2 interacts with either receptor in a ligand-dependent manner, suggesting that Foxa2 and the receptor bind DNA as an interdependent complex during ligand activation. Furthermore, PPARα binding is induced in Foxa2 mutants treated with FXR and LXR ligands, leading to activation of PPARα targets.

2021-07-12 | GSE149075 | GEO

Fxr signaling and microbial metabolism of bile salts in the zebrafish intestine

Project description:The purpose of this study was to elucidate potential effects of fxr mutation on the functional specification of intestinal epithelial cells. To do this, we sorted GFP-positive cells from TgBAC(cldn15la:GFP) transgenics of either fxr+/+ or fxr-/- fish larvae and subjected them to 10X Genomics single-cell RNA-seq. Our results uncovered the requirement of fxr in gene expression and differentiation among multiple intestinal epithelial cell types.

2021-04-30 | GSE173570 | GEO

Postprandial FGF19 signaling-induced phosphorylation of FXR by Src modulates its activity in bile acid homeostasis

Project description:Farnesoid-X-Receptor (FXR) plays a central role in maintaining bile acid (BA) homeostasis by transcriptional control of numerous enterohepatic genes, including intestinal FGF19, a hormone that strongly represses hepatic BA synthesis. How activation of the FGF19 receptor at the membrane is transmitted to the nucleus for transcriptional regulation of BA levels and whether FGF19 signaling posttranslationally modulates function of FXR remain largely unknown. Here we show that FXR is phosphorylated at Y67 by non-receptor tyrosine kinase, Src, in response to postprandial FGF19, which is critical for its nuclear localization and transcriptional regulation of BA levels. Liver-specific expression of phospho-defective Y67F-FXR or Src-downregulation in mice result in impaired homeostatic responses to acute BA feeding, and exacerbate cholestatic pathologies upon drug-induced hepatobiliary insults. Also, the hepatic FGF19-Src-FXR pathway is defective in primary biliary cirrhosis patients. This study identifies Src-mediated FXR phosphorylation as a potential therapeutic target and biomarker for BA-related enterohepatic diseases.

2018-04-27 | GSE113707 | GEO

Gene expression analysis of FXR null, SHP null, and double FXR/SHP null mice

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

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