Studies on the mechanisms underlying Angiopoietin-like 4-induced epidermal stem cell proliferation
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ORGANISM(S): Mus musculus
PROVIDER: GSE282348 | GEO | 2024/11/20
REPOSITORIES: GEO
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Project description:Studies on the mechanisms underlying Angiopoietin-like 4-induced epidermal stem cell proliferation
| PRJNA1188169 | ENA
Project description:Helicobacter pylori (H. pylori) infection is characterized as progressive processes of bacterial persistence and chronic gastritis with features of infiltration of mononuclear cells more than granulocytes in gastric mucosa. Angiopoietin-like 4 (ANGPTL4) is considered a double-edged sword in inflammation-associated diseases, but its function and clinical relevance in H. pylori-associated pathology is unknown. Here we demonstrate both pro-colonization and pro-inflammation roles of ANGPTL4 in H. pylori infection. Increased ANGPTL4 in the infected gastric mucosa was produced from gastric epithelial cells (GECs) synergistically induced by H. pylori and IL-17A in a cagA-dependent manner. Human gastric ANGPTL4 correlated with H. pylori colonization and the severity of gastritis, and mouse ANGPTL4 from non-bone marrow-derived cells promoted bacteria colonization and inflammation. Importantly, H. pylori colonization and inflammation were attenuated in Il17a-/-, Angptl4-/-, Il17a-/-Angptl4-/- mice. Mechanistically, ANGPTL4 bound to integrin αV (ITGAV) on GECs to suppress CXCL1 production by inhibiting ERK, leading to decreased gastric influx of neutrophils, thereby promoting H. pylori colonization; ANGPTL4 also bound to ITGAV on monocytes to promote CCL5 production by activating PI3K-AKT-NF-κB, resulting in increased gastric influx of regulatory CD4+ T cells (Tregs) via CCL5-CCR4-dependent migration. In turn, ANGPTL4 induced Treg proliferation through binding to ITGAV to activate PI3K-AKT-NF-κB, promoting H. pylori-associated gastritis. Overall, we propose a model in which ANGPTL4 collectively ensures H. pylori persistence and promotes gastritis. Efforts to inhibit ANGPTL4-associated pathway may prove valuable strategies in treating H. pylori infection.
2024-05-15 | GSE266891 | GEO
Project description: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.
2013-03-11 | GSE40706 | GEO
Project description:Despite recent advances, rheumatoid arthritis (RA) patients remain refractory to therapy. Dysregulated overproduction of angiopoietin-like protein 4 (ANGPTL4) is thought to contribute to the disease development. ANGPTL4 was initially identified as a regulator of lipid metabolism, which is hydrolyzed to N-terminal and C-terminal (cANGPTL4) fragments in vivo. cANGPTL4 is involved in several non-lipid-related processes, including angiogenesis and inflammation. This study revealed that the level of ANGPTL4 was markedly elevated in the sera and synovial tissues from patients with RA versus controls. The administration of a neutralizing antibody against cANGPTL4 (anti-cANGPTL4 Ab) resulted in the inhibition of inflammatory processes and bone loss in animal models of collagen-induced arthritis and adjuvant-induced arthritis (AIA). Transcriptomic and proteomic profiling of synovial tissues from an AIA model indicated that the anti-cANGPTL4 Ab inhibited fibroblast-like synoviocyte (FLS) immigration and inflammatory-induced osteoclastogenesis. Mechanistically, the anti-cANGPTL4 Ab has been shown to inhibit TNF-α-induced inflammatory cascades in RA-FLS through the sirtuin 1/nuclear factor-κB signaling pathway. Moreover, the anti-cANGPTL4 Ab was found to block FLS invasion- and immigration-induced osteoclast activation. Collectively, these findings identify ANGPTL4 as a prospective biomarker for the diagnosis of RA, and targeting cANGPTL4 should represent a potential therapeutic strategy.
2024-10-24 | GSE276556 | GEO
Project description:<p><strong>OBJECTIVE: </strong>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.</p><p><strong>METHODS: </strong>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.</p><p><strong>RESULTS: </strong>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.</p><p><strong>CONCLUSIONS: </strong>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.</p>
2023-11-15 | MTBLS4082 | MetaboLights
Project description:Analysis of changes in skeletal muscle myoblasts in response to over-expression of angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2). The hypothesis tested in the present study was that over-expression of Ang-1 or Ang-2 will induce the expression of pro-survival and pro-differentiation genes in skeletal myoblasts while inhibiting the expression of pro-apoptotic genes. Results provide important information of how mRNA profile of skeletal myoblasts is altered by Ang-1 and ang-2 and provide first evidence that secondary mediators such as leptin may mediate the enhancement of skeletal myoblasts differentiation by Ang-1 and Ang-2. Total RNA obtained from isolated human skeletal myoblasts after 48hrs of infection with adenoviruses expressing GFP (control), Ang-1 or Ang-2.
2012-05-23 | E-GEOD-29508 | biostudies-arrayexpress
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
Project description:Despite recent advances, rheumatoid arthritis (RA) patients remain refractory to therapy. Dysregulated overproduction of angiopoietin-like 4 protein (ANGPTL4) is thought to be contributed to the disease development. Therefore, interference with ANGPTL4 biological function may constitute a new therapeutic strategy for this disease. ANGPTL4 was initially identified as a regulator of lipid metabolism, which is hydrolyzed to N-terminal (nANGPTL4) and C-terminal (cANGPTL4) fragments in vivo. cANGPTL4 is involved in several non-lipid-related processes, including angiogenesis and inflammation. In this study, we analyzed the mRNA expression of ANGPTL4 in synovial tissue of RA in comparison to healthy individuals of the Gene Expression Omnibus (GEO) database. The results indicated that the mRNA expression of ANGPTL4 is increased in RA synovial tissues. The level of ANGPTL4 was found to be overexpressed in the sera and synovial tissues from patients with RA versus controls. A neutralizing antibody against cANGPTL4 (anti-cANGPTL4 Ab) was employed to treat arthritis animal models, including collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA), respectively. The results demonstrated that the anti-cANGPTL4 Ab inhibited inflammation and bone loss in two models. Transcriptomic and proteomic profiling of synovial tissues from AIA model indicated that the anti-cANGPTL4 Ab inhibited fibroblast-like synoviocyte (FLS) immigration and inflammatory-induced osteoclastogenesis. These data collectively identify ANGPTL4 as a potential biomarker for the diagnosis of RA, and targeting cANGPTL4 may represent a novel therapeutic strategy.
2024-09-05 | PXD055569 |
Project description:Angiopoietin-Tie2 sytem has been inplicated in both vascular quiescence and angiogenesis. It is unclear how these two opposing signals are regulated from the same receptor-mediated intracellular signal transduction. We have noticed that Tie2 localization upon Angiopoietin stimulation depends upon the presence or absence of cell-cell contacts. Therefore, to identify the downstream signaling of Tie2 upon Angiopoietin stimulation, we performed DNA microarray analyais using RNAs obtained from confluent human umbirical vein endothelial cells (HUVECs) or sparse HUVECs stimulated with after Angiopoietin-1. There is striking difference on gene expression profile between confluent and sparse HUVECs. Experiment Overall Design: To identify the genes in HUVECs which are upregulated or downregulated by the stimulation with Angiopoietin-1 in the presence (confluent) or absence (sparse) of cell-cell contacts, mRNAs were prepared from either confluent HUVECs or sparse HUVECs stimulated or unstimulated with 100 ng/ml COMP-Ang1 (more potent Angiopoietin-1). RNAs were obtained from HUVECs three times cultured independently three times and mixed as one RNA sample for further DNA microarray analyses. Experiment Overall Design: Microarray (Human Genome U133 Plus 2.0 array, Affymetrix) analyses have been performed in duplicate. Biotin labeled probes were used for the series of analyses. Hybridization and Scan were performed according to the recommendation by Affymetric. Data have been processed following the MAS 5.0 with target intensity = 100.
2008-06-16 | E-GEOD-9677 | biostudies-arrayexpress
Project description:Angiopoietin-Tie2 sytem has been inplicated in both vascular quiescence and angiogenesis. It is unclear how these two opposing signals are regulated from the same receptor-mediated intracellular signal transduction. We have noticed that Tie2 localization upon Angiopoietin stimulation depends upon the presence or absence of cell-cell contacts. Therefore, to identify the downstream signaling of Tie2 upon Angiopoietin stimulation, we performed DNA microarray analyais using RNAs obtained from confluent human umbirical vein endothelial cells (HUVECs) or sparse HUVECs stimulated with after Angiopoietin-1. There is striking difference on gene expression profile between confluent and sparse HUVECs. Keywords: endothelial cell, angiopoietin
2008-04-01 | GSE9677 | GEO