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Gut microbiota-induced perturbations in bile acids alter keratinocyte lipid metabolism via FXR-NQO1 signaling in psoriasis

ABSTRACT: Emerging evidence has shown that microbiota dysbiosis and aberrant bile acids (BAs) profiles are correlated with disease progression. This study elucidates dysregulated BAs metabolism in psoriasis patients and imiquimod-treated female mice, coupled with increased expression of the farnesoid X receptor (FXR) in keratinocytes. Activation of FXR by glycochenodeoxycholic acid (GCDCA) ameliorates psoriatic symptoms by enhancing lipid metabolism, particularly fatty acid oxidation. Mechanistically, the arrow_drop_downmore

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase, Liquid Chromatography MS - alternating - reverse-phase

PROVIDER: MTBLS14191 | MetaboLights | 2026-03-31

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS14191_LC-MS_alternating_reverse-phase.txt	Txt
	a_MTBLS14191_LC-MS_negative_reverse-phase.txt	Txt
	a_MTBLS14191_LC-MS_positive_reverse-phase.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS14191_LC-MS_alternating_reverse-phase_v2_maf.tsv	Tabular

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Similar Datasets

Gut microbiota-induced perturbations in bile acids alter keratinocyte lipid metabolism via FXR-NQO1 signaling in psoriasis

Project description:Emerging evidence has shown that microbiota dysbiosis and aberrant bile acids (BAs) profiles are correlated with disease progression. This study elucidates dysregulated BAs metabolism in psoriasis patients and imiquimod-treated female mice, coupled with increased expression of the farnesoid X receptor (FXR) in keratinocytes. Activation of FXR by glycochenodeoxycholic acid (GCDCA) ameliorates psoriatic symptoms by enhancing lipid metabolism, particularly fatty acid oxidation. Mechanistically, the FXR-mediated enhancement of antioxidant capacity by upregulating NAD(P)H quinone dehydrogenase 1 (NQO1) expression underlies its regulatory role in lipid metabolism, offering an insight into FXR’s role in oxidative stress and lipid metabolism. Conversely, keratinocyte-specific FXR ablation exacerbates psoriasis severity. Gut microbiota dysbiosis is further identified as a pivotal contributor to perturbations in BA profiles in psoriasis. These findings support a mechanistic model linking gut microbiota and BA alterations to FXR signaling in keratinocytes and psoriasis-associated metabolic dysregulation, suggesting therapeutic potential for microbiota-targeted interventions.

2026-03-29 | MTBLS14183 | MetaboLights

Altered mRNA expression profile of GW4064 treated mouse livers compared to vehicle control

2014-07-24 | GSE57305 | GEO

Altered mRNA expression profile of GW4064 treated mouse livers compared to vehicle control

Project description:Farnesoid X receptor (FXR) is a ligand activated nuclear receptor belonging to the nuclear receptor superfamily. Bile acids (BAs) are the endogenous ligand for FXR. FXR is a master regulator of BA homestasis, including BA synthesis, metabolism, transport, and enterohepatic circulation of BAs. Besides, FXR is involved in regulating diverse physioligical function in both humans and mice. GW4064 is a synthetic FXR agonist which selectively activates FXR and induce the transcription of FXR target genes. In this study, we treated wild type C57BL/6J mice with GW4064 at 100mg per kg body weight or vehicle control. Mice were treated three times, first dose at 8 am, second dose at 6 pm, third dose at 8 am the second day. Mice were sacrificed 2 hours after the last dose, and liver tissues were harvested for analysis. Animal protocols and procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Kansas Medical Center. Total RNA from livers was prepared with TRIzol Reagent (Invitrogen, CA), and the whole transcription expression levels were determined using Mouse Gene 1.0 ST Array system manufactured by Affymetrix, Inc..

2014-07-24 | E-GEOD-57305 | biostudies-arrayexpress

Microbial Bile Acid Metabolism Shapes T Cell Responses During Inflammation

Project description:Microbial transformation of bile acids (BAs) affects intestinal immune homeostasis but the impact of changes in BA metabolism on T cell-driven pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that GVHD decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of microbiota-dependent unconjugated and secondary BAs (SBAs). Several SBAs attenuated farnesoid X receptor (FXR) activity, posing that loss of SBAs may increase FXR activation and exacerbate inflammation. Mortality in GVHD mice increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and SBAs. Moreover, the FXR antagonist ursodeoxycholic acid reduced the activation of human T cells and was associated with a reduced risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of SBAs may be an important mechanism to amplify T cell-mediated diseases.

2023-06-28 | MSV000092300 | MassIVE

Transcriptional response of human duodenal enteroid monolayers to norovirus infection

Project description:The goal of this study was to evaluate the transcriptional response of 4 human duodenal enteroid lines on monolayers to norovirus infections (GII.4). Enteroids were plated as monolayers in Intesticult (Stem Cell Technologies) proliferation medium. After 1 day of cell growth as a monolayer, the proliferation medium was changed with differentiation medium for 5 days. Five-day-differentiated monolayers were washed and were either mock-infected or inoculated with human norovirus supplemented with 500 μM glycochenodeoxycholic acid (GCDCA), for 1 to 2 h at 37°C. Total RNA was extracted using the Qiagen RNeasy kit and paired-end Illumina sequencing was performed.

2021-10-01 | GSE183223 | GEO

Ursodeoxycholic acid alleviates aortic aneurysm and dissection through the intestinal farnesoid X receptor/ceramide synthesis 2 axis

Project description:The farnesoid X receptor (FXR) is a nuclear receptor mainly expressed in the liver and intestine. In the intestine, FXR plays a crucial role in regulating lipid metabolism, bile acid homeostasis, and intestinal barrier function.Activation of FXR can lead to the regulation of a variety of genes involved in these processes. For example, it can affect the absorption and transport of lipids and bile acids through the intestine,in this paper,we Ursodeoxycholic acid alleviates aortic aneurysm and dissection through the intestinal farnesoid X receptor/ceramide synthesis 2 axis.

2025-05-10 | GSE280869 | GEO

FXR splicing by SF3B3 promotes MYC-driven hepatocarcinogenesis

Project description:BACKGROUND AND AIMS: Dysregulation of the MYC oncogene is a major genetic event in hepatocellular carcinoma (HCC). Farnesoid X receptor (FXR), a bile acid (BA) receptor, has emerged as a promising therapeutic target for various liver diseases. Both BA composition and FXR isoforms have been shown to be significantly altered in human HCCs. This study aimed to investigate their potential roles in MYC-driven hepatocarcinogenesis. APPROACH AND RESULTS: HCC was induced in mice by hydrodynamic injection with MYC and MCL1 oncogenes. UPLC-MS/MS analysis revealed elevated BA levels, particularly primary conjugated BAs, in both serum and livers of MYC-driven HCC mice. qPCR and western blot analyses demonstrated suppression of BSEP and dysregulation of FXR splicing in the livers of these mice. Using RNA antisense purification coupled with mass spectrometry (RAP-MS), the splicing factor SF3B3 was identified as a regulator of FXR splicing. Both in silico and in vitro studies confirmed that SF3B3 is a direct downstream target of MYC in mice and humans. Functionally, overexpression of Fxrα2 and Fxrα4 or deletion of Sf3b3 significantly impeded MYC-driven hepatocarcinogenesis in mice. Moreover, combination treatment with a SF3B inhibitor and an FXR agonist synergistically suppressed proliferation of HCC cells. Analysis of clinical HCC samples revealed a positive correlation between SF3B3 and the relative expression of FXRα2. Conclusions: SF3B3 is a key downstream effector of MYC-driven hepatocarcinogenesis and a critical regulator of FXR splicing. Both SF3B3 and FXR represent druggable vulnerabilities in MYC-amplified HCC.

2025-10-02 | GSE309158 | GEO

Prevention of cholestatic liver disease through BCL6-FXR enterohepatic crosstalk

Project description:Bile acid (BA) metabolism must be tightly regulated because BAs serve as metabolic signaling molecules but become cytotoxic at high levels. The farnesoid X receptor (FXR) is a crucial bile acid sensor, but our understanding of its regulation and coordination with other transcription factors is limited. Here, we found that B cell lymphoma 6 (Bcl6) functions along with FXR to control bile acid levels. We found that mice lacking hepatic BCL6 (Bcl6LKO) had increased BA synthesis and serum levels. In line with this, Bcl6LKO mice had elevated serum cholesterol, the upstream substrate for BA synthesis, as well as reduced expression of the hepatic BA re-uptake transporter sodium-taurocholate cotransporting polypeptide (NTCP). Furthermore, loss of BCL6 reduced hepatic fibroblast growth factor 4 (FGFR4) expression, causing dysregulated entero-hepatic BA feedback signaling. To better understand the relative contribution of BCL6 and FXR in regulating BA homeostasis, we generated mice with a combined deletion of hepatic BCL6 and FXR (Bcl6LKOFxrKO). Critically, combined deletion of FXR and hepatic BCL6 caused massive elevations in BA synthesis/levels compared to loss of Fxr or Bcl6 alone, which resulted in cholestatic liver damage. Mechanistically, we found that Bcl6LKO FxrKO mice had an almost complete loss of hepatic Shp expression, causing high levels of the rate-limiting BA synthesis enzyme CYP7A1. Together, these findings demonstrate that BCL6 and FXR function together to limit BA synthesis and protect the liver from cholestatic injury.

2026-02-11 | GSE296552 | GEO

Prevention of cholestatic liver disease through BCL6-FXR enterohepatic crosstalk [RNA-seq]

2026-02-11 | GSE290309 | GEO

Prevention of cholestatic liver disease through BCL6-FXR enterohepatic crosstalk [ChIP-seq]

2026-02-11 | GSE290307 | GEO