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Short-chain fatty acids stimulate angiopoietin-like 4 synthesis in human colonocytes by selective PPARγ modulation

ABSTRACT: Angiopoietin-like protein 4 (ANGPTL4, also referred to as Fiaf) has been proposed as a circulating mediator between the gut microbiota and fat storage in adipose tissue. Very little is known about the mechanisms of regulation of ANGPTL4 in the colon. Here we show that transcription and subsequent secretion of ANGPTL4 in human T84 and HT-29 colonocytes is highly induced by physiological concentrations of products of bacterial fermentation, the short-chain fatty acids. Short-chain fatty acids induce ANGPTL4 by activating the nuclear receptor PPARγ, as shown by microarray, transactivation assays, coactivator peptide recruitment assay, and use of PPARγ antagonist. At concentrations required for PPARγ activation and ANGPTL4 induction in colonocytes, SCFA do not stimulate PPARγ in mouse 3T3-L1 and human SGBS adipocytes, suggesting that SCFA act as selective PPARγ modulators (SPPARM), which is supported by coactivator peptide recruitment assay and structural modelling. It can be concluded that 1) SCFA potently stimulate ANGPTL4 synthesis in human colonocytes, and 2) SCFA transactivate and bind to PPARγ by serving as selective PPAR modulators. Our data point to activation of PPARγ as a novel mechanism of gene regulation by SCFA in the colon.

ORGANISM(S): Homo sapiens

PROVIDER: GSE40706 | GEO | 2013/03/11

SECONDARY ACCESSION(S): PRJNA174693

REPOSITORIES: GEO

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Short chain fatty acids induce ANGPTL4 via PPARγ

Project description:Angiopoietin-like protein 4 (ANGPTL4, also referred to as Fiaf) has been proposed as circulating mediator between the gut microbiota and fat storage in adipose tissue. Very little is known about mechanisms of regulation of ANGPTL4 in the colon. Here we show that transcription and subsequent secretion of ANGPTL4 in human T84 and HT-29 colonocytes is highly induced by physiological concentrations of products of bacterial fermentation, the short chain fatty acids (SCFA). Induction of ANGPTL4 by SCFA cannot be mimicked by the histone deacetylase inhibitor Trichostatin A. SCFA induce ANGPTL4 by activating the nuclear receptor PPARγ, as shown by use of PPARγ antagonist, PPARγ knock-down, and transactivation assay, which shows activation of PPARγ but not PPARα and PPARδ. At concentrations required for PPARγ activation and ANGPTL4 induction in colonocytes, SCFA do not stimulate PPARγ in mouse 3T3-L1 and human SGBS adipocytes, suggesting that SCFA act as selective PPARγ modulators (SPPARM), which is supported by coactivator peptide recruitment assay and structural modelling. Consistent with the notion that fermentation leads to PPAR activation in vivo, feeding mice a diet rich in inulin was associated with induction of PPAR target genes and pathways in the colon, as shown by microarray and subsequent gene set enrichment analysis. It can be concluded that 1) SCFA potently stimulate ANGPTL4 synthesis in human colonocytes; 2) SCFA transactivate and bind to PPARγ by serving as selective PPAR modulators. Our data point to activation of PPARγ as a novel mechanism of gene regulation by SCFA in the colon.

2013-03-11 | GSE43065 | GEO

Mus musculus

Project description:Short chain fatty acids induce ANGPTL4 via PPARγ

| PRJNA184303 | ENA

Homo sapiens

Project description:Short-chain fatty acids stimulate angiopoietin-like 4 synthesis in human colonocytes by selective PPARγ modulation

| PRJNA174693 | ENA

Angiopoietin-like 4 governs diurnal lipoprotein lipase activity in brown adipose tissue.

Project description:OBJECTIVE: Brown adipose tissue (BAT) burns fatty acids (FAs) to produce heat, and shows diurnal oscillation in glucose and triglyceride (TG)-derived FA-uptake, peaking around wakening. Here we aimed to gain insight in the diurnal regulation of metabolic BAT activity.METHODS: RNA-sequencing, chromatin immunoprecipitation (ChIP)-sequencing and lipidomics analyses were performed on BAT samples of wild type C57BL/6J mice collected at 3-h intervals throughout the day. Knockout and overexpression models were used to study causal relationships in diurnal lipid handling by BAT.RESULTS: We identified pronounced enrichment of oscillating genes involved in extracellular lipolysis in BAT, accompanied by oscillations of FA and monoacylglycerol content. This coincided with peak lipoprotein lipase (Lpl) expression, and was predicted to be driven by peroxisome proliferator-activated receptor gamma (PPARγ) activity. ChIP-sequencing for PPARγ confirmed oscillation in binding of PPARγ to Lpl. Of the known LPL-modulators, angiopoietin-like 4 (Angptl4) showed the largest diurnal amplitude opposite to Lpl, and both Angptl4 knockout and overexpression attenuated oscillations of LPL activity and TG-derived FA-uptake by BAT.CONCLUSIONS: Our findings highlight involvement of PPARγ and a crucial role of ANGPTL4 in mediating the diurnal oscillation of TG-derived FA-uptake by BAT, and imply that time of day is essential when targeting LPL activity in BAT to improve metabolic health.

2023-11-15 | MTBLS4082 | MetaboLights

Gut microbiome metabolites alter genomic networks in PC12 cells relevant to autism spectrum diorders

Project description:Alterations in the composition of the gut microbiome have an emerging role in brain function and behaviour. We have porposed that short chain fatty acids (SCFA) including propionate and butyrate which are present in the diet and are fermantation products of many gastrointestinal bacteria are contributing environmental factors in autism spectrum disorders (ASD). Here we used the microarray technology to compare global changes in gene expression profiles following exposure of PC12 cells to structurally related SCFA propionate and butyrate each in two different concentrations. Large number of affected genes, common for both SCFA were identified, including genetic networks and GO processes implicated in ASD. PC12 cells were exposed to propionate or butyrate. RNA was isolated from each experimental group (n=6, pooled samples) and subjected to genome-wide expression profiling using Affymetrix microarrays to reveal dose- and SCFA-specific changes in gene expression and specific molecular pathways or processes affected as compared to vehicle treated controls.

2014-06-02 | E-GEOD-56516 | biostudies-arrayexpress

Gut microbiome metabolites alter genomic networks in PC12 cells relevant to autism spectrum diorders

2014-06-02 | GSE56516 | GEO

A phase I study of a 5-peptide vaccine with immune modulators for patients with refractory metastatic colorectal cancer

Project description:Interventions: 1)Immune modulators, composed of cyclophosphamide, metformin, celecoxib and cimetidine are administered orally for 1 week 2)Induction phase: 5-peptide cocktail vaccine weekly in combination with immune modulators are administered for 8 weeks 3)Maintenance phase: 5-peptide cocktail vaccine biweekly in combination with immune modulators are administered for 8 weeks 4)Extension phase: maintenance therapy is allowed depending on patient condition Primary outcome(s): The safety of the immune modulators with/without 5-peptide cocktail vaccine Study Design: Single arm Non-randomized

| 2641385 | ecrin-mdr-crc

Insights into microbial modulation of host peripheral lipid and glucose metabolism using mouse gut organoids

Project description:The gastrointestinal microbiota is involved in the development of various diseases, such as obesity and diabetes, by affecting nutrient acquisition, energy balance, and metabolic signaling of the host. However, the underlying mechanisms of these host-microbiota interactions remain unclear. The aim of this study was to characterize effects of the microbiota on the host epithelium using a novel gastrointestinal model based on mouse organoids. We have explored the transcriptional response of organoids upon exposure to short chain fatty acids (SCFA) and products generated by two conspicuous members of the gastrointestinal microbiota; Akkermansia muciniphila and Faecalibacterium prausnitzii. We observed that A. muciniphila metabolites affect a large variety of transcription factors and genes involved in cellular lipid metabolism and growth, supporting previous in vivo findings. F. prausnitzii products exerted only a weak effect on the host transcription profile. While, A. muciniphila, and its main metabolite propionate, both stimulate fasting-induced adipose factor/angiopoietin-like protein 4 (Fiaf/Angptl4) and Ppar? expression, important regulators of lipolysis and satiety. This work illustrates that specific members of the microbiota and their metabolites differentially modulate epithelial transcription in mouse organoid lines.

2014-07-23 | GSE59644 | GEO

Enterohemorrhagic Escherichia coli: impact of short chain fatty acid treatment on virulence gene expression

Project description:transcriptome analysis of enterohemorrhagic E. coli treated with either one of two different concentrations of short chain fatty acid mixes or the corresponding sodium chloride osmolarity control four conditions: 30mM SCFA mix; 30mM NaCl control; 172mM SCFA mix: 172 mM NaCl control. Biological replicates: 4 per group

2016-03-23 | E-GEOD-79509 | biostudies-arrayexpress

Proteolytic processing converts pro-tumorigenic Angiopoietin-like 4 into an inhibitor of metastasis

Project description:Preclinical and clinical studies have solidly established the concepts of concomitant tumor resistance (CTR), the inhibition of metastases formation by the primary tumor. Yet, the mechanisms of CTR are poorly understood and bench-to-bedside studies are largely missing. Here, we show that proteolytic processing of ANGPTL4 liberated the potent CTR-inducing capacity of the N-terminal cleavage fragment, nANGPTL4. Full-length ANGPTL4 was primarily detected in tumor tissues, whereas nANGPTL4 predominated in the systemic circulation, whose concentrations correlated inversely with disease progression. Comparative studies in multiple preclinical tumor models revealed distinctly opposing functions of the ANGPTL4 cleavage fragments. Full length and cANGPTL4 promoted tumor growth and metastasis leading to reduced overall survival. Conversely, nANGPTL4 inhibited metastasis formation and enhanced overall survival. The experiments identified proteolytic cleavage as regulatory mechanism converting pro-tumorigenic ANGPTL4 into anti-metastatic nANGPTL4. Moreover, the results revitalize the concept that primary tumors may suppress metastases through systemic release of metastasis-inhibiting cytokines

2022-10-17 | PXD020269 | Pride

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