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

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

ORGANISM(S): Mus musculus

PROVIDER: GSE113549 | GEO | 2018/08/16

REPOSITORIES: GEO

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

| PRJNA451493 | ENA

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

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

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

| PRJNA453136 | ENA

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

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]

| PRJNA451436 | ENA

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

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

Hepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism

Project description:A greater understanding of the glucose homeostasis mediated by glucagon-like peptide-1 (GLP-1) will facilitate the development of novel glucose-lowering treatments. Here we show that improved glucose metabolism in hypothyroid mice after treatment of T3, the active form of thyroid hormone (TH), is accompanied with increased GLP-1 production and insulin secretion. Treatment of a GLP-1 receptor antagonist is able to attenuate the observed T3 effect on insulin and glucose levels, suggesting that GLP-1 is critically involved in the regulation of glucose homeostasis by T3. By using a mouse model lacking hepatic TH receptor β (TRβ) and a liver-specific TRβ-selective agonist, we demonstrate that TRβ-mediated hepatic TH signalling is not only required for the regulation of GLP-1 production by T3 but also the insulinotropic and glucose-lowering effects of T3. Accordingly, administration of the liver-targeted TRβ-selective agonist is capable of increasing GLP-1 and insulin levels and alleviating hyperglycemia in diet-induced obesity. Mechanistically, through suppressing CYP8B1 expression, T3 shapes the bile acid (BA) composition and increases the levels of Farnesoid X receptor (FXR)-antagonistic BAs, thereby potentiating the GLP-1 production and insulin secretion by repressing intestinal FXR signalling. Consistently, correlations between the T3 levels and either GLP-1 or FXR-antagonistic BA levels can be observed in euthyroid human subjects. Thus, our study reveals a previously undescribed role of hepatic TH signalling in glucose homeostasis through the regulation of GLP-1 production via BA-mediated FXR antagonism, which will underpin the development of novel therapeutics.

2022-09-23 | GSE184055 | 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

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