The essential roles of FXR in diet and aging affected metabolic changes and liver disease development: a multi-omics study
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ABSTRACT:
PROVIDER: PRJNA893365 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22016600_1.fastq.gz | Fastqsanger.gz | |||
| SRR22016600_2.fastq.gz | Fastqsanger.gz | |||
| SRR22016601_1.fastq.gz | Fastqsanger.gz | |||
| SRR22016601_2.fastq.gz | Fastqsanger.gz | |||
| SRR22016602_1.fastq.gz | Fastqsanger.gz |
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Project description:Aging and unhealthy diets are risks for metabolic diseases including liver cancer. Bile acid receptor farnesoid X receptor (FXR) knockout (KO) mice develop metabolic liver diseases and progress into liver cancer as they age, and Western diet (WD) intake facilitates liver carcinogenesis in those mice. This study aimed to uncover molecular signatures within the gut-liver axis for diet and age-linked liver diseases in FXR-dependent or independent manners. Many more transcripts were changed due to WD intake and aging in WT mice than those in FXR KO mice. In other words, WD intake and aging impact the hepatic transcriptomes and metabolomes in an FXR-dependent manner. In WT mice, WD/aging upregulated inflammation-related genes and downregulated genes involved in oxidative phosphorylation (OXPHOS). Urine metabolomes provided clear distinguishing for differential dietary intake. By contrast, the metabolomes of the liver, serum, or urine could reflect age differences. Further, irrespective of differential diets intake or ages, transcriptomes, metabolomes, and cecal microbiota distinguished WT and FXR KO. Western dietary patterns and aging share molecular commonality with FXR deactivation. Notably, WD, aging, and FXR deactivation commonly altered hepatic cell division-related transcripts (Cenpe, Ect2, Top2a, Kif20a, Tpx2, Nuf2, Kif18b, Aspm, E2f8, and Hmmr), which are associated with overall survival rate in HCC patients. In conclusion, FXR is essential for maintaining metabolic homeostasis in response to WD intake and aging. FXR activation helps to alleviate diet and/or aging-induced metabolic health issues.
2023-02-22 | GSE216375 | GEO
Project description: Not available
| S-EPMC9938992 | biostudies-literature
Project description:Cancer-associated fibroblasts (CAFs), the principal components of tumor microenvironment, play multiple roles in breast cancer onset and progression. While their impact is widely accepted, treatment options to target CAFs in clinical practice were not yet well established. The nuclear receptor superfamily encompasses a druggable class of molecules, expressed in various stroma and parenchymal cell types, with the interesting therapeutic potential to modulate the reactive microenvironment. Having already addressed the oncosuppressive role of the nuclear Farnesoid X Receptor (FXR) in mammary epithelial cancer cells, the present study is aimed to assess the function of FXR in CAFs and evaluate whether its activation may affect their tumor-promoting features.
2018-12-31 | E-MTAB-6343 | biostudies-arrayexpress
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
Project description:The roles of the farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) in regulating metabolic pathways were highlighted recently. Nevertheless, the impact of FXR inhibitors on glucose metabolism remains unclear. In this study, we explored the effects of 7β-isopropylchenodeoxycholic acid (7β-ipCDCA), a combined FXR antagonist and TGR5 agonist, on impaired glucose metabolism in mice fed Western diet. A dual FXR antagonistic/TGR5 agonistic activity of 7β-ipCDCA was confirmed on gene reporter assays. Its effects on glucose homeostasis were evaluated using a glucose tolerance test in C57BL/6J mice mimicking metabolic syndrome condition induced by Western diet with additional sugar in drinking water for 24 weeks. The glucose-lowering mechanism was investigated by measuring glucagon-like peptide 1 (GLP-1) release, mRNA expression of glucose transporters and genes involved in glucose metabolism in intestinal, hepatic, white adipose, and kidney tissues, and in human intestinal NCI-H716 and murine GLUTag cells. Additionally, bile acid metabolome and liver lipidome were determined. 7β-ipCDCA restored blood glucose homeostasis altered by Western diet in mice via enhanced GLP-1 release and inhibition of glucose transporters in the ileum. While changes in the liver function were marginal, 7β-ipCDCA augmented taurocholic acid plasma concentration. 7β-ipCDCA increased liver triglycerides exclusively in mice fed a chow diet, whereas mice on the Western diet were protected from hepatic triglyceride accumulation. This study revealed a novel role of FXR in regulating intestinal glucose transporters and GLP-1 secretion, emphasizing the potential of FXR antagonists/TGR5 agonists in modulating hyperglycemia.
2025-09-20 | GSE291059 | GEO
Project description:WT and Fxr-/- mouse primary hepatocytes were treated with FAC or AC for 24 h. The transcriptome profiling (RNA-seq) analysis revealed that FXR plays critical roles in regulating iron homeostasis.
2023-11-20 | GSE161863 | GEO
Project description:The bile-acid receptor FXR is known to be expressed in both intestine and liver, and FXR agonists are currently Under clinical evaluation for Metabolic Associated SteatoHepatitis (MASH) treatment. However, the specific question about activate or de-activate FXR specifically in the intestine in MASH is still unlear, protective results being available for both case. We used micro-arrays to identify both liver and intestine transcriptome alterations led by intestinal FXR deletion in the context of MASH
2026-06-09 | GSE318026 | GEO
Project description:The Farnesoid-X-Receptor (FXR) is a class II nuclear receptor (NR), a class that obligately heterodimerizes with the Retinoid-X-Receptor (RXR). FXR is expressed as 4 isoforms (α1-α4) activated by bile acids that drive transcription from response elements IR-1 (inverted repeat-1). We recently showed that FXR isoforms α2 and α4 bind to non-canonical response elements ER-2 (everted repeat-2), thereby increasing mitochondrial respiratory capacity and limiting de novo lipogenesis. Binding to ER-2 motifs in mouse liver organoids represented 89% of all FXR genome wide binding. However, mechanistic differences in FXR binding and activation from these two response elements remained unexplored. Using DNA pull down followed by mass-spectrometry, we show that RXR is not involved in FXR binding to ER-2 response elements. Instead, RXR inhibited FXR binding and activation from these elements in luciferase reporters. Genome wide, RXR-lacking FXR binding sites showed higher enrichment for ER-2 motifs in mouse liver. Pharmacological and mutational abrogation of FXR-RXR heterodimerization specifically retained ER-2 transactivation capacities in luciferase reporters and HepG2 cells. Transcriptome-wide, 25% of FXR targets were inhibited upon RXR overexpression, but specifically activated by a novel heterodimerization-deficient mutant FXRα2L434R. These genes were ER-2 responsive and were involved in lipid metabolism and ammonia detoxification. In conclusion, we discovered that RXR is not required and even inhibits binding of FXRα2 to ER-2. Thus, whereas FXR α1 and α3 seem to be genuine class II NR, FXRα2 and α4 are facultative class II at ER-2 motifs. This novel feature holds promise to exploit and tailor therapeutic responses to FXR agonism.
2024-11-12 | PXD047930 | Pride
Project description:The bile-acid receptor FXR is known to be expressed in both intestine and liver, and FXR agonists are currently Under clinical evaluation for Metabolic Associated SteatoHepatitis (MASH) treatment. However, the specific question about activate or de-activate FXR specifically in the intestine in MASH is still unlear, protective results being available for both case.
2026-06-09 | GSE318468 | GEO
Project description:FXR (Farnesoid X Receptor), also known as Nr1h4, is a transcription factor who is also one of the bile acid receptor has been reported to be widely involved in regulating blood glucose, bile acid, and the apoptosis of hepatocyte. We have been studing the key role of FXR in Type 2 Diabetes, which can regulate the insulin secretion or even the apoptosis of β-cells. Thus,we measured the gene expression in the islets of FXR KO mice. Our data shows the abnormal expressed gene between the FXR KO mice and the Control group, which may be regulated by FXR. It will be significant promotion for the research in mechanism of FXR regulating the insulin secretion and apoptosis of β-cells.
2024-12-12 | GSE279682 | GEO