C/EBPβ regulates lipid metabolism and Pparg isoform 2 expression in alveolar macrophages
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA727756 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14456923_1.fastq.gz | Fastqsanger.gz | |||
| SRR14456923_2.fastq.gz | Fastqsanger.gz | |||
| SRR14456924_1.fastq.gz | Fastqsanger.gz | |||
| SRR14456924_2.fastq.gz | Fastqsanger.gz | |||
| SRR14456925_1.fastq.gz | Fastqsanger.gz |
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Project description:Tissue resident macrophages are a heterogeneous population with unique functions. During steady state conditions most tissue macrophages are of embryonic origin and maintained locally. Despite their common fetal origin, tissue macrophages are able to fulfil tissue specific functions, suggesting that the local environment can modulate cell function. It has been reported that PPARg is critical for the development of macrophages in the lung. Here, we show that PPARg functions as a transcriptional repressor in alveolar macrophages. Alveolar macrophages lacking Pparg responded more strongly to LPS stimulation by producing more cytokines and phagocytosed more particles in vitro. Certain prostaglandins can act as endogenous ligands for PPARg. We show that prostaglandins were expressed in an organ-specific fashion and modulated cytokine production by alveolar macrophages as well as bone marrow-derived macrophages and monocytic U937 cells. Pparg expression was further induced in macrophages by different cytokine combinations including IL-4, IL-3 and IL-13 suggesting a global role for PPARg which can be regulated by the local environment on two levels. Lastly, repression of inflammatory genes was mediated by PPARg interacting with NFkB and STAT signalling cascades rather than direct transrepression. Therefore PPARg is a modulator of macrophage functions, that changes the inflammatory state of macrophages by regulating classical immune signalling cascades.
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Project description:Peroxisome proliferator-activated receptor-gamma (PPARg) regulates the interface between cellular lipid metabolism, redox status and organelle differentiation. Following conditional prostatic epithelial knockout of PPARg in mice we observed focal hyperplasia of the epithelium which developed to mouse prostatic intraepithelial neoplasia (mPIN), becoming progressively more severe with time. We selectively knocked down PPARg2 isoform in wild-type mouse prostatic epithelial cells and examined the consequences of this in a tissue recombination model. Histopathologically the results resembled the conditional PPARg KO mouse prostates. Electron microscopy showed accumulated defective lysosomes and autophagic vacuoles in both of PPARg- and g2- deficient cells. Gene expression profiling indicated a major dysregulation of cell cycle control and metabolic signaling networks related to peroxisomal and lysosomal maturation, lipid oxidation and degradation. We conclude that PPARg maintains the maturation and turnover of peroxisomes and lysosomes in prostate epithelium. Disruption of PPARg signaling results in autophagy and oxidative stress during mPIN pathogenesis. The mPrE-PPARg knockout and mPrE-PPARg2 shRNA cells were compared to wildtype mPrE cells. Time (3 days culture) and cell types (x 4) were tested.
2010-05-18 | E-GEOD-13867 | biostudies-arrayexpress
Project description:Peroxisome proliferator-activated receptor-gamma (PPARg) regulates the interface between cellular lipid metabolism, redox status and organelle differentiation. Following conditional prostatic epithelial knockout of PPARg in mice we observed focal hyperplasia of the epithelium which developed to mouse prostatic intraepithelial neoplasia (mPIN), becoming progressively more severe with time. We selectively knocked down PPARg2 isoform in wild-type mouse prostatic epithelial cells and examined the consequences of this in a tissue recombination model. Histopathologically the results resembled the conditional PPARg KO mouse prostates. Electron microscopy showed accumulated defective lysosomes and autophagic vacuoles in both of PPARg- and g2- deficient cells. Gene expression profiling indicated a major dysregulation of cell cycle control and metabolic signaling networks related to peroxisomal and lysosomal maturation, lipid oxidation and degradation. We conclude that PPARg maintains the maturation and turnover of peroxisomes and lysosomes in prostate epithelium. Disruption of PPARg signaling results in autophagy and oxidative stress during mPIN pathogenesis.
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Project description:Macrophages exhibit a reparative phenotype that supports tissue repair and remodeling in response to tissue injury. However, the metabolic requirements that support this process have remained incompletely understood. Here, we showed that posttranslational modification (PTM) of peroxisome proliferator-activated receptor g (PPARg) regulated lipid synthesis in response to wound microenvironmental cues and that metabolic rewiring orchestrated the function of reparative macrophages. In injured tissues, repair signaling attenuated macrophage PPARg threonine 166 (T166) phosphorylation, which induced a partially active PPARg program with increased binding activity to the regulator regions of lipid synthesis-associated genes, thereby activating lipogenesis. The accumulated lipids served as signaling molecules, triggering signal transducer and activator of transcription 3 (STAT3)-mediated growth factor expression, and supporting the synthesis of phospholipids for the expansion of the endoplasmic reticulum (ER), which is required for the secretion of proteins. Genetic or pharmacological inhibition of PPARg T166 phosphorylation promoted the reparative function of macrophages and facilitated tissue regeneration. In summary, we identified that PPARg T166-regulated lipid biosynthesis was essential for the anabolic demands of the activation and function of macrophages and provided a rationale for therapeutic targeting of tissue repair.
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