Loss of phospholipase PLAAT3 causes lipodystrophy due to impaired PPAR signaling
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE233433 | GEO | 2023/05/30
REPOSITORIES: GEO
Similar Datasets
Project description:PLAAT3 is a phospholipid modifying enzyme predominantly expressed in neural and white adipose tissue (WAT). It is a potential drug target for metabolic syndrome as Plaat3 deficiency in mice protects against diet-induced obesity. We identified seven patients from four unrelated consanguineous families, with homozygous loss-of-function variants in PLAAT3, presenting a severe lipodystrophy syndrome (LS) associated with metabolic complications, as well as neurological features including demyelinating neuropathy and intellectual disability. Multi-omics analysis of mouse Plaat3-/- and patient-derived WAT showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in the signaling of PPAR?, the master regulator of adipocyte differentiation. The present dataset describes the proteomics shotgun analysis of WAT samples from Plaat3-/- and Plaat3-/+ mice. We found that proteins involved in fatty acid metabolic and lipid biosynthetic processes were less abundant in Plaat3-/- WAT, whereas proteins involved in autophagy and catabolism were more abundant. In line with transcriptomics data obtained from mice and human WAT, PPAR? and its coactivators were identified as strong transcriptional regulators within the set of downregulated proteins. Along with validation experiments in PLAAT3-deficient human adipose stem cells, these findings establish PLAAT3 deficiency as a novel hereditary LS with neurological manifestations, caused by a PPAR?-dependent defect in WAT differentiation and function.
2023-08-29 | PXD038815 | Pride
Project description:Adipocytes are the primary sites for fatty acid storage, but the synthesis rate of fatty acids is very low. The physiological significance of this phenomenon remains unclear. Here, we show that surplus fatty acid synthesis in adipocytes induces necroptosis and lipodystrophy. Transcriptional activation of FASN elevates fatty acid synthesis, but decreases NADPH level and increases ROS production, which ultimately leads to adipocyte necroptosis. We identify MED20, a subunit of the Mediator complex, as a negative regulator of FASN transcription. Adipocyte-specific male Med20 knockout mice progressively develop lipodystrophy, which is reversed by scavenging ROS. Further, in a murine model of HIV-associated lipodystrophy and a human patient with acquired lipodystrophy, ROS neutralization significantly improves metabolic disorders, indicating a causal role of ROS in disease onset. Our study well explains the low fatty acid synthesis rate in adipocytes, and sheds light on the management of acquired lipodystrophy.
2023-12-11 | GSE249808 | GEO
Project description:The phosphatidylinositol 3 kinase (PI3K) pathway regulates fundamental cellular processes such as metabolism, proliferation, and survival. A central component in this pathway is the p85? regulatory subunit, encoded by PIK3R1. Using whole-exome sequencing, we identified a heterozygous PIK3R1 mutation (c.1945C>T [p.Arg649Trp]) in two unrelated families affected by partial lipodystrophy, low body mass index, short stature, progeroid face, and Rieger anomaly (SHORT syndrome). This mutation led to impaired interaction between p85? and IRS-1 and reduced AKT-mediated insulin signaling in fibroblasts from affected subjects and in reconstituted Pik3r1-knockout preadipocytes. Normal PI3K activity is critical for adipose differentiation and insulin signaling; the mutated PIK3R1 therefore provides a unique link among lipodystrophy, growth, and insulin signaling.
| S-EPMC3710758 | biostudies-literature
Project description:Background and objective: Combination antiretroviral therapy (cART) is associated with lipodystrophy i.e. loss of subcutaneous adipose tissue in abdomen, limbs and face and its accumulation intra-abdominally. No fat is lost dorsocervically and it can even accumulates in this region (“buffalo hump”). It is unknown how preserved dorsocervical fat differs from abdominal subcutaneous fat in HIV-1-infected cART-treated patients with (cART+LD+) and without (cART+LD-) lipodystrophy. Results: Albeit dorsocervical adipose tissue in cART+LD+ seems spared from lipoatrophy, its mitochondrial DNA (mtDNA, copies/cell) content was significantly lower (by 62%) than that of the corresponding tissue in cART+LD-. Expression of CD68 mRNA, a marker of macrophages, and numerous inflammatory genes in microarray were significantly lower in dorsocervical vs. abdominal subcutaneous adipose tissue. Genes with the greatest difference in expression between the two depots were those involved in regulation of transcription and regionalization (homeobox genes), irrespective of lipodystrophy status. There was negligible mRNA expression of uncoupling protein 1, a gene characteristic of brown adipose tissue, in either depot. Conclusions: As mtDNA is depleted even in the non-atrophic dorsocervical adipose tissue, it is unlikely that the cause of lipoatrophy is loss of mtDNA. Dorsocervical adipose tissue is less inflamed than lipoatrophic adipose tissue. It does not resemble brown adipose tissue. The greatest difference in gene expression between dorsocervical and abdominal s.c. adipose tissue is in expression of homeobox genes. We used histology, microarray, polymerase chain reaction and magnetic resonance imaging to compare dorsocervical and abdominal subcutaneous adipose tissue in cART+LD+ (n=21) and cART+LD- (n=11). The study consists of 17 patients on antiretroviral treatment who have developed lipodystrophy and 11 patients that are on similar treatment but have not developped lipodystrophy. All patients are HIV+ and have 2 adipose tissue samples taken from them (dorsocervical+abdominal).
2011-09-14 | E-GEOD-28073 | biostudies-arrayexpress
Project description:In this setup we have used RNA-seq, ChIP-seq, and ATAC-seq to identify how natural mutations in PPARg, which leads to lipodystrophy, cause changes in transcription, chromatin landscape, transcription factor binding and enhancer activity.
2022-10-27 | GSE199426 | GEO
Project description:Genome wide DNA methylation profiling of Congenital Lipodystrophy type 2 patients, mutation carriers , and healthy control samples .The Infinium MethylationEPIC Kit was used to measure genome-wide DNA methylation across > 868,000 CpG sites.
2023-08-08 | GSE214297 | GEO
Project description:Analysis of inguinal white adipose tissue (WAT) isolated from wildtype (WT) and Notch1 overexpression mice (Ad/NICD). Results provide insight into molecular mechanisms underlying lipodystrophy of Ad/NICD mice
2016-08-28 | GSE80215 | GEO
Project description:The peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation, and mutations that interfere with PPARγ function cause lipodystrophy. Structural studies indicate that PPARγ domains engage in several intra- and inter-moleuclar interactions; however, how these interactions modulate the ability of PPARγ to activate target genes in a cellular context is currently poorly understood. Here we analysed the transcriptional potential of R212Q and E379K two previously uncharacterised lipodystrophy-associated PPARγ mutants that are located in distinct PPARγ domains but are both predicted to affect intermolecular interactions. Using a combination of biochemical and genome-wide approaches we show that these mutations impair binding to an overlapping subset of enhancers that are less accessible and specifically require PPARγ for chromatin remodeling. Based on these findings we propose a model in which recruitment of PPARγ to chromatin is determined by several intermolecular interfaces. Furthermore, our data exemplify that relatively subtle molecular defects in transcription factors are sufficient to significantly affect enhancer binding and thereby transcriptional output.
2022-09-08 | PXD036589 | Pride
Project description:The regulation of phospholipid biosynthesis in Saccharomyces cerevisiae through cis-acting upstream activating sequence inositol (UASino) and trans-acting elements, such as the INO2-INO4 complex and OPI1 by inositol supplementation in growth is thoroughly studied. In this study, we provide evidence for the regulation of lipid biosynthesis by phosphatidylinositol-specific phospholipase C (PLC) through UASino and two trans-acting elements. Gene expression analysis and radiolabelling experiments demonstrated that the overexpression of rice PLC in yeast cells altered phospholipid biosynthesis at the levels of transcriptional and enzyme activity. There are two biological replicates two hour and five hour induction with galactose. The genome wide expression of Saccharomyces cerevisiae strain BY4741 harbouring rPLC-pYES2 and a vectro control (pYES2) were compare with each other. (Agilent Gene Expression Saccharomyces cerevisiae 8x15k array AMADID: 016333)
2012-04-23 | E-GEOD-35677 | biostudies-arrayexpress
Project description:The regulation of phospholipid biosynthesis in Saccharomyces cerevisiae through cis-acting upstream activating sequence inositol (UASino) and trans-acting elements, such as the INO2-INO4 complex and OPI1 by inositol supplementation in growth is thoroughly studied. In this study, we provide evidence for the regulation of lipid biosynthesis by phosphatidylinositol-specific phospholipase C (PLC) through UASino and two trans-acting elements. Gene expression analysis and radiolabelling experiments demonstrated that the overexpression of rice PLC in yeast cells altered phospholipid biosynthesis at the levels of transcriptional and enzyme activity. There are two biological replicates two hour and five hour induction with galactose. The genome wide expression of Saccharomyces cerevisiae strain BY4741 harbouring (rice) rPLC-pYES2 and a vectro control (pYES2) were compare with each other. (Agilent Gene Expression Saccharomyces cerevisiae 8x15k array AMADID: 016333)
2012-09-01 | E-GEOD-35745 | biostudies-arrayexpress