Characterization of ANGPTL4 function in macrophages and adipocytes using Angptl4-knockout and Angptl4-hypomorphic mice
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PROVIDER: PRJNA561718 | ENA |
REPOSITORIES: ENA
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Project description:ANGPTL4 regulates plasma lipids, making it an attractive target for correcting dyslipidemia. However, ANGPTL4 inactivation in mice fed a high fat diet causes chylous ascites, an acute-phase response, and mesenteric lymphadenopathy. Here, we studied the role of ANGPTL4 in lipid uptake in macrophages and in the above-mentioned pathologies using Angptl4-hypomorphic and Angptl4-/- mice. Angptl4 expression in peritoneal and bone marrow-derived macrophages was highly induced by lipids. Recombinant ANGPTL4 decreased lipid uptake in macrophages, whereas deficiency of ANGPTL4 increased lipid uptake, upregulated lipid-induced genes, and increased respiration. ANGPTL4 deficiency did not alter LPL protein levels in macrophages. Angptl4-hypomorphic mice with partial expression of a truncated N-terminal ANGPTL4 exhibited reduced fasting plasma triglyceride, cholesterol, and non-esterified fatty acid levels, strongly resembling Angptl4-/- mice. However, during high fat feeding, Angptl4-hypomorphic mice showed markedly delayed and attenuated elevation in plasma serum amyloid A and much milder chylous ascites than Angptl4-/- mice, despite similar abundance of lipid-laden giant cells in mesenteric lymph nodes. In conclusion, ANGPTL4 deficiency increases lipid uptake and respiration in macrophages without affecting LPL protein levels. Compared with the absence of ANGPTL4, low levels of N-terminal ANGPTL4 mitigate the development of chylous ascites and an acute-phase response in mice.
2019-08-24 | GSE136240 | GEO
Project description:Angiopoietin-like protein (ANGPTL)4 regulates plasma lipids, making it an attractive target for correcting dyslipidemia. However, ANGPTL4 inactivation in mice fed a high fat diet causes chylous ascites, an acute-phase response, and mesenteric lymphadenopathy. Here, we studied the role of ANGPTL4 in lipid uptake in macrophages and in the above-mentioned pathologies using Angptl4-hypomorphic and Angptl4 -/- mice. Angptl4 expression in peritoneal and bone marrow-derived macrophages was highly induced by lipids. Recombinant ANGPTL4 decreased lipid uptake in macrophages, whereas deficiency of ANGPTL4 increased lipid uptake, upregulated lipid-induced genes, and increased respiration. ANGPTL4 deficiency did not alter LPL protein levels in macrophages. Angptl4-hypomorphic mice with partial expression of a truncated N-terminal ANGPTL4 exhibited reduced fasting plasma triglyceride, cholesterol, and NEFAs, strongly resembling Angptl4 -/- mice. However, during high fat feeding, Angptl4-hypomorphic mice showed markedly delayed and attenuated elevation in plasma serum amyloid A and much milder chylous ascites than Angptl4 -/- mice, despite similar abundance of lipid-laden giant cells in mesenteric lymph nodes. In conclusion, ANGPTL4 deficiency increases lipid uptake and respiration in macrophages without affecting LPL protein levels. Compared with the absence of ANGPTL4, low levels of N-terminal ANGPTL4 mitigate the development of chylous ascites and an acute-phase response in mice.
| S-EPMC6795085 | biostudies-literature
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
Project description:Protracted inflammatory responses are signatures common to many gastrointestinal disorders. Severe and chronic disorders often bring about extensive tissue damage, in turn leading to hypercytokinemia. Here, we show that stimuli like dextran sulphate sodium salt (DSS) and stearic acid (SA) cause acute colonic inflammation, and ANGPTL4 is an important regulator in mediating the extent of colonic inflammation. Using comparative microarray gene expression analysis, we seek to identify genes whose expression are altered during inflammation between ANGPTL4+/+ and ANGPTL4-/- mice.
2017-03-28 | GSE78500 | GEO
Project description:Bcl11b hypomorphic mutant thymocytes
| PRJNA356604 | ENA
Project description:This study aims to identify miRNA molecules that are involved in inflammatory response in macrophages. A miRNA expression profiling of mouse macrophages comparing control wild type cells with DICER hypomorphic cells were conducted after these were subjected to treatment with LPS. Keywords: miRNA; DICER hypomorphic macrophages, microarray Pairwise comparison of Control versus DICER1 (Dcr1) hypomorphic cells. Two biological replicates were performed with three technical replicates for each biological replicate: 1 Control, 1 DICER1 (Dcr1) hypomorph, 2 treatment conditions. Exposed to LPS, harvested at 2hr and 4hr post treatment.
2010-10-31 | E-GEOD-12699 | biostudies-arrayexpress
Project description:This study aims to identify miRNA molecules that are involved in inflammatory response in macrophages. A miRNA expression profiling of mouse macrophages comparing control wild type cells with DICER hypomorphic cells were conducted after these were subjected to treatment with LPS. Keywords: miRNA; DICER hypomorphic macrophages, microarray
2010-10-31 | GSE12699 | GEO
Project description:Angiopoietin-like 4 (ANGPTL4) is known to regulate various cellular and systemic functions. However, its cell-specific role in endothelial cells (ECs) function and metabolic homeostasis remains to be elucidated. Here, using endothelial-specific Angptl4 knock-out mice (Angptl4iEC), and transcriptomics and metabolic flux analysis, we demonstrate that ANGPTL4 is required for maintaining EC metabolic function vital for vascular permeability and angiogenesis. Knockdown of ANGPTL4 in ECs promotes lipase-mediated lipoprotein lipolysis, which results in increased fatty acid (FA) uptake and oxidation. This is also paralleled by a decrease in proper glucose utilization for angiogenic activation of ECs. Mice with endothelial-specific deletion of Angptl4 showed decreased pathological neovascularization with stable vessel structures characterized by increased pericyte coverage and reduced permeability. Together, our study denotes the role of endothelial-ANGPTL4 in regulating cellular metabolism and angiogenic functions of EC.
2023-11-22 | GSE211128 | GEO
Project description:Leptin protein was thought to be unique to leptin receptor (LepR), but the phenotypes of mice with mutation in LepR (db/db) and leptin (ob/ob) are not identical, and the cause remains unclear. Here, we show that db/db, but not ob/ob mice had defect in tenotomy-induced heterotopic ossification (HO), implicating alternative ligand(s) for LepR might be involved. Ligand screening revealed that ANGPTL4, a stress and fasting-induced factor, was elicited from brown adipose tissue after tenotomy, bound to LepR on PRRX1+ mesenchymal cells at the HO cite, thus promotes chondrogenesis and HO development. Disruption of LepR in PRRX1+ cells, or lineage ablation of LepR+ cells, or deletion of ANGPTL4 impeded chondrogenesis and HO in mice. Surprisingly, exogenous ANGPTL4 treatment not only promoted HO, but facilitated the transformation from white to brown adipose tissue in mice. These findings identify ANGPTL4 as a novel ligand for LepR to stimulate HO and regulate fat metabolism.
2024-07-03 | PXD043087 | Pride
Project description:Renal cell carcinoma (RCC), the most common form of kidney cancer, is a heterogeneous disease with clear cell RCC (ccRCC) being the most prevalent and aggressive subtype. While most ccRCC tumors have elevated expression of angiopoietin-like 4 (ANGPTL4), in our study we identified a significant subset of patients whose cancers show no increase in ANGPTL4 expression. These patients have a worse prognosis compared to the patients with high expression of ANGPTL4. These ANGPTL4-low cancers are characterized by the increased frequency of wild-type Von Hippel-Lindau (wt VHL), a gene that is commonly mutated in ccRCC, and an enrichment for genes associated with lipid metabolism. Using RCC tumor models with wild type VHL, we demonstrate that ANGPTL4 behaves as a tumor suppressor. The loss of ANGPTL4 in ccRCC cell lines results in increased tumor growth and colony formation in a lysosomal acid lipase (LAL)-dependent manner, a phenotype rescued by the expression of N-terminus ANGPTL4. At the mechanistic level, the loss of ANGPTL4 increases lysosomal acid lipase activity in ccRCC cells. This data suggests that ANGPTL4 enacts its tumor-suppressive effects in ccRCC by regulating LAL activity. Importantly, the identified patient cohort with low ANGPTL4 expression may exhibit increased reliance on lipid metabolism, which can be a point of target for future therapy.
2024-07-30 | GSE273236 | GEO