Altered pattern of circulating miRNAs in HIV lipodystrophy perturbs key adipose differentiation and inflammation pathways
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA762058 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15832877.fastq.gz | Fastqsanger.gz | |||
| SRR15832878.fastq.gz | Fastqsanger.gz | |||
| SRR15832879.fastq.gz | Fastqsanger.gz | |||
| SRR15832880.fastq.gz | Fastqsanger.gz | |||
| SRR15832881.fastq.gz | Fastqsanger.gz |
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Project description:We identified a microRNA (miRNA) profile characterizing HIV lipodystrophy and explored the downstream mechanistic implications with respect to adipocyte biology and the associated clinical phenotype. Human preadipocytes transfected with mimic miR-20a-3p, anti–miR-324-5p, or anti–miR-186 induced consistent changes in latent transforming growth factor beta binding protein 2 (Ltbp2), Wisp2, and Nebl expression.
2021-09-22 | GSE183822 | GEO
Project description:We identified a microRNA (miRNA) profile characterizing HIV lipodystrophy and explored the downstream mechanistic implications with respect to adipocyte biology and the associated clinical phenotype. miRNA profiles were extracted from small extracellular vesicles (sEVs) of HIV-infected individuals with and without lipodystrophic changes and individuals without HIV, among whom we previously showed significant reductions in adipose Dicer expression related to HIV. miR-20a-3p was increased and miR-324-5p and miR-186 were reduced in sEVs from HIV lipodystrophic individuals. Changes in these miRNAs correlated with adipose Dicer expression and clinical markers of lipodystrophy, including fat redistribution, insulin resistance, and hypertriglyceridemia. Human preadipocytes transfected with mimic miR-20a-3p, anti-miR-324-5p, or anti-miR-186 induced consistent changes in latent transforming growth factor beta binding protein 2 (Ltbp2), Wisp2, and Nebl expression. Knockdown of Ltbp2 downregulated markers of adipocyte differentiation (Fabp4, Pparγ, C/ebpa, Fasn, adiponectin, Glut4, CD36), and Lamin C, and increased expression of genes involved in inflammation (IL1β, IL6, and Ccl20). Our studies suggest a likely unique sEV miRNA signature related to dysregulation of Dicer in adipose tissue in HIV. Enhanced miR-20a-3p or depletion of miR-186 and miR-324-5p may downregulate Ltbp2 in HIV, leading to dysregulation in adipose differentiation and inflammation, which could contribute to acquired HIV lipodystrophy and associated metabolic and inflammatory perturbations.
| S-EPMC8492307 | biostudies-literature
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: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: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: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:Adipocyte hypertrophy during obesity triggers chronic inflammation, leading to metabolic disorders. However, the role of adipocyte-specific inflammatory signalling in metabolic syndrome remains unclear. The linear ubiquitin chain assembly complex, LUBAC, is an E3-ligase that generates non-degradative linear ubiquitination (Lin-Ub). LUBAC regulates NF-κB/MAPK-driven inflammation and prevents cell death triggered by immune receptors like TNF-receptor-1. Here we show that mice lacking HOIP, LUBAC’s catalytic subunit, in adipocytes (HoipA-KO) display lipodystrophy and heightened susceptibility to obesity-induced metabolic syndrome, particularly Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Mechanistically, loss of HOIP attenuates TNF-induced NF-κB activation and promotes cell death in human adipocytes. Inhibiting caspase-8-mediated cell death is sufficient to prevent lipodystrophy and MASLD in HoipA-KO obese mice. Importantly, HOIP expression in adipose tissue positively correlates with metabolic fitness in obese individuals. Overall, our findings reveal a fundamental developmental role for Lin-Ub in adipocytes by mitigating cell death-driven adipose tissue inflammation and protecting against obesity-related metabolic
2025-08-22 | GSE298555 | GEO
Project description:Adipocyte hypertrophy during obesity triggers chronic inflammation, leading to metabolic disorders. However, the role of adipocyte-specific inflammatory signalling in metabolic syndrome remains unclear. The linear ubiquitin chain assembly complex, LUBAC, is an E3-ligase that generates non-degradative linear ubiquitination (Lin-Ub). LUBAC regulates NF-κB/MAPK-driven inflammation and prevents cell death triggered by immune receptors like TNF-receptor-1. Here we show that mice lacking HOIP, LUBAC’s catalytic subunit, in adipocytes (HoipA-KO) display lipodystrophy and heightened susceptibility to obesity-induced metabolic syndrome, particularly Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Mechanistically, loss of HOIP attenuates TNF-induced NF-κB activation and promotes cell death in human adipocytes. Inhibiting caspase-8-mediated cell death is sufficient to prevent lipodystrophy and MASLD in HoipA-KO obese mice. Importantly, HOIP expression in adipose tissue positively correlates with metabolic fitness in obese individuals. Overall, our findings reveal a critical role for Lin-Ub in protecting against obesity-related metabolic syndrome by mitigating cell death-driven adipose tissue inflammation
2025-09-03 | GSE293034 | GEO
Project description:Lipodystrophy (LD) indicates a group of rare disorders, with generalized or partial loss of white adipose tissue (WAT) often associated with metabolic derangements. Heterogeneity/wide spectrum of the disease and lack of biomarkers make diagnosis often difficult. MicroRNAs are important to maintain a correct WAT function and WAT is a source of circulating miRNAs (cmiRs). miRNAs from 320 family were previously detected in the WAT and variably associated to the metabolic syndrome. Our aim was then to investigate if LD can result in altered abundance of cmiRs-320. We collected samples from a cohort of LD subjects of various subtypes and from age matched controls. Use of quantitative PCR determined that cmiRs- 320a-3p, 320b, 320c, 320e are upregulated, while 320d is downregulated in LD. CmiRs-320 power as classifiers was more powerful in the most extreme and defined forms of LD, including the generalized and the Dunnigan subtypes. cmiR-320a-3p showed significant inverse relationships with plasma leptin (P < 0.0001), typically low in LD. The hepatic enzymes gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and the marker of inflammation C-reactive protein (CRP) were inversely related to cmiR 320d (P < 0.05, for CRP and GGT; P < 0.01, for AST and ALT). Gene ontology analysis revealed cell-cell adhesion as a process regulated by 320 miRNAs targets, thus disclosing a novel route to investigate origin of WAT loss/dysfunction. In conclusion, cmiRs-320 constitute novel biomarkers of LD, abundance of miR320a-3p is inversely associated to indicators related to WAT function, while downregulation of cmiR-320d predicts an altered hepatic profile and higher inflammation.
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