The bile acid CoA ligase, FATP5, is necessary for NAT synthesis in the liver
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina NovaSeq 6000
ORGANISM(S): Mus musculus
SUBMITTER: Single Cell Omics Platform CBMR
PROVIDER: E-MTAB-15752 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Fatty acid amide hydrolase (FAAH) is an important enzyme for lipid metabolism and an interesting pharmacological target, given its role in anandamide breakdown. The FAAH-/- genotype is the most widely used mouse model to achieve complete abolition of this enzyme. In this paper we explore, by means of label-free SWATH proteomics, the changes in protein expression occurring in the liver of FAAH-/- mice. We identified several altered biological processes and pathways, like fatty acid synthesis and glycolysis, which explain the observed phenotype of this mouse. We also observed the alteration of other proteins, like carboxylesterases and S-methyltransferases, apparently not immediately related to FAAH, but known to have important biological roles.
2018-08-20 | PXD010087 | Pride
Project description:Benson2014 - FAAH inhibitors for the treatment of osteoarthritic pain
Evaluation of fatty acid amide hydrolase (FAAH) as a target for osteoarthritic pain in humans, using an integrated systems pharmacology model.
The SBML version of the model is obtained from the supplementary material of the corresponding paper (see below).
This model is described in the article:
A systems pharmacology perspective on the clinical development of Fatty Acid amide hydrolase inhibitors for pain.
Benson N, Metelkin E, Demin O, Li GL, Nichols D, van der Graaf PH.
CPT Pharmacometrics Syst Pharmacol. 2014 Jan 15;3:e91.
Abstract:
The level of the endocannabinoid anandamide is controlled by fatty acid amide hydrolase (FAAH). In 2011, PF-04457845, an irreversible inhibitor of FAAH, was progressed to phase II clinical trials for osteoarthritic pain. This article discusses a prospective, integrated systems pharmacology model evaluation of FAAH as a target for pain in humans, using physiologically based pharmacokinetic and systems biology approaches. The model integrated physiological compartments; endocannabinoid production, degradation, and disposition data; PF-04457845 pharmacokinetics and pharmacodynamics, and cannabinoid receptor CB1-binding kinetics. The modeling identified clear gaps in our understanding and highlighted key risks going forward, in particular relating to whether methods are in place to demonstrate target engagement and pharmacological effect. The value of this modeling exercise will be discussed in detail and in the context of the clinical phase II data, together with recommendations to enable optimal future evaluation of FAAH inhibitors.
This model is hosted on BioModels Database
and identified
by: MODEL1402030000
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
2024-09-02 | BIOMD0000000512 | BioModels
Project description:N-acyl taurines (NAT) are endogenous, bioactive conjugates of fatty acids and taurine with roles in glucose and lipid metabolism. In the liver, NATs share the taurine conjugation enzyme, bile acid-CoA:amino acid N-acyltransferase (BAAT), with bile acids, suggesting the potential of an overlapping hepatic synthesis pathway. However, the remaining enzymes involved in NAT production in the liver remain unknown. This study aimed to investigate the overlap between hepatic NAT and bile acid synthesis to identify additional enzymes involved in NAT synthesis in the liver. Using transcriptomics of livers with altered NAT metabolism, we identified Slc27a5 which encodes fatty acid transport protein 5 (FATP5), as a potential node in the pathway. Knocking down the enzyme using siRNA in vivo confirmed that FATP5 is necessary for hepatic NAT synthesis and upstream of BAAT, likely through its acyl-CoA synthetase activity. The dual functions of this enzyme in activating both fatty acids and bile acids for conjugation implies functional overlap between the hepatic NAT and bile acid production pathway.
2026-02-27 | PXD070306 | Pride
Project description:Clinical management of breast cancer (BC) metastasis remains an unmet need as it accounts for 90% of BC-associated mortality. Although the luminal subtype, which represents >70% of BC cases, is generally associated with a favorable outcome, it is susceptible to metastatic relapse as late as 15 years after treatment discontinuation. Seeking therapeutic approaches as well as screening tools to properly identify those patients with a higher risk of recurrence is therefore essential. Here, we report that the lipid-degrading enzyme fatty acid amide hydrolase (FAAH) is a predictor of long-term survival in patients with luminal BC, and that it blocks tumor progression and lung metastasis in cell and mouse models of BC. Together, our findings highlight the potential of FAAH as a biomarker with prognostic value in luminal BC and as a therapeutic target in metastatic disease.
2022-03-09 | GSE197984 | GEO
Project description:The experiment was performed on 10 lactating laboratory mice (Mus musculus, MF1). Half of the mice were shaved to increase their capacity to dissipate body heat (and thus milk production), while the other half were unshaved controls. By RNA-seq profiling of the mammary gland in shaved and unshaved lactating mice, we identified differentially expressed genes (DEGs) associated with shaving and then compared them with three sets of genes compiled from the mouse mammary gland literature, containing 1) imprinted genes, 2) milk synthesis-related genes, and 3) involution-related genes. Finally, DEGs induced by shaving were subjected to functional analysis of gene expression, with the focus on canonical pathways, upstream regulators, and downstream effects. We demonstrated that the shaving-induced increases in milk production were not associated with the changes in the expression of imprinted or milk-synthesis related genes. Instead, several lines of evidence strongly suggest that the mammary gland of shaved mice went into involution earlier than that of unshaved mice. Our interpretation of these results is that once provided with the enhanced capacity to dissipate body heat, shaved mice were able to rear their young to independence faster than unshaved mothers, benefiting potentially from shorter lactation and shorter interbirth interval to maximise their lifetime reproductive success.
2022-12-31 | E-MTAB-11654 | biostudies-arrayexpress
Project description:Population-based studies show cannabis use doubles the risk of developing schizophrenia especially when use occurs in early adolescence (prior to age 15). However, the cause-and-effect mechanisms are largely unknown. To investigate the effect of cannabis on brain maturation and relation to the development of psychosis-like behaviours in adulthood, we treated young adolescent mice with vehicle or cannabis extract once a day for 2 weeks between postnatal days 14 and 28, and then collected hippocampal tissue for microarray analysis 12 weeks later. We identify a total of 78 differentially expressed genes (25 upregulated and 53 downregulated; p<0.05, fold change ± 1.2) and validate increases in dopamine D2 receptor (Drd2) and fatty acid amide hydrolase (Faah). Changes in Faah expression were limited to the hippocampus however Drd2 also increased in striatum but not prefrontal cortex or amygdala. When tested in adulthood with a behavioural panel relevant to schizophrenia, cannabis-treated mice displayed lower anxiety in the elevated zero-maze, decreased social preference, increased social novelty preference, mild cognitive impairments in a spatial version of the novel object recognition task and absence of latent inhibition when compared to vehicle controls. Adolescent treatment with cannabis extract thus lead to long-lasting changes in gene expression within the hippocampus which together result in behavioural deficits consistent with the negative and positive symptoms of schizophrenia.
2018-02-17 | GSE58437 | GEO
Project description:We determined the gene expression changes by URB597, a fatty acid amide hydrolase inhibitor, treatment.
2020-01-07 | GSE143194 | GEO
Project description:Multiple metabolic enzymes that classically function in cytosolic or mitochondrial pathways have recently been documented within cell nuclei, where they can directly impact gene expression and therefore cell phenotypes. Thus, the cell nucleus has emerged as an active site of metabolism. However, metabolites can passively diffuse across nuclear pores, and the extent to which the nucleus and cytosol are continuous versus distinct metabolic compartments remains unclear. Both the nucleus and cytosol require acetyl-CoA for specific processes (e.g., histone acetylation and lipid synthesis, respectively), and the acetyl-CoA producing enzyme ATP-citrate lyase (ACLY) is present in both locations, yet the biological significance of its nuclear-cytosolic distribution is incompletely understood. Here, we leveraged cell lines in which ACLY is restricted to either the nucleus or cytosol to investigate its compartmentalized functions. We find that ACLY in either location can support both fatty acid synthesis and histone acetylation, but compartment-localized ACLY enables fine-tuning of both processes. Nuclear ACLY preserves histone H3K23 acetylation under glucose limitation and modulates specific transcriptional programs, including suppression of fatty acid and cholesterol synthesis genes. Conversely, cytosolic ACLY most efficiently supports fatty acid synthesis and elongation, reflecting both local substrate production and increased expression of lipogenic enzymes. The data indicate that metabolites such as acetyl-CoA can diffuse between the nucleus and cytosol, but that local synthesis defines a preferential metabolic fate for products, enabling finer control of cellular processes.
2025-11-26 | GSE310990 | GEO
Project description:Background: Radiation-induced intestinal injury (RIII) represents a significant dose-limiting complication of radiotherapy, characterized by substantial loss of intestinal epithelial cells (IECs). While the activation of cannabinoid receptor 2 (CB2R) is protective in immune‑mediated colitis, the intrinsic role of CB2R in IECs and its potential therapeutic relevance in RIII have not been defined. Methods: An RIII mouse model was established in wild-type and CB2R-/- mice. Small-molecule CB2R agonists were screened for radioprotective efficacy, followed by pharmacological and siRNA-based interrogation of CB2R signaling in intestinal epithelial cell lines and primary mouse intestinal epithelial cells. RNA sequencing and bioinformatics were combined with permeability assays, immunofluorescence, electron microscopy, and molecular analyses of oxidative stress and ferroptosis to elucidate underlying mechanisms. Results: Irradiation induced CB2R expression in the intestinal epithelium, and genetic ablation of CB2R markedly aggravated RIII. A focused pharmacological screen identified a recently synthesized dual‑target compound, CB2R/FAAH modulator‑2 (CF‑2), which combines CB2R agonistic activity with fatty acid amide hydrolase (FAAH) inhibition and significantly mitigated radiation‑induced colonic injury while exerting protective effects on the small intestine and spleen. Mechanistically, CB2R activation attenuated irradiation‑induced ferroptosis and preserved intestinal epithelial integrity. Integrative transcriptomic analyses identified Homeobox A10 (HoxA10) as a critical epithelial‑enriched transcriptional amplifier that reinforced CB2R/β‑catenin signaling through a positive‑feedback loop, thereby enhancing CB2R‑mediated epithelial protection. Conclusions: This study defines an epithelial‑intrinsic CB2R signaling axis in RIII, linking ferroptosis suppression to preservation of intestinal barrier integrity. CF‑2 is positioned as a promising mechanism‑based candidate for radioprotection.
2026-04-22 | GSE328344 | GEO
Project description:The development of therapeutic anticancer vaccines calls for the identification of tumor-specific antigens (TSAs). Though a combination of four cutting-edge proteogenomic approaches, we performed a deep exploration of the MHC-I presented peptides (MAPs) of 19 acute myeloid leukemia (AML) patients and identified various TSAs that could serve for the design of an anti-AML vaccine.
2021-03-19 | PXD018542 | Pride