FABP4 Contributes to Preeclampsia Through Dysregulating Lipid Metabolism and Inducing Mitochondrial Oxidative Stress in Trophoblasts
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE306887 | GEO | 2026/03/25
REPOSITORIES: GEO
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Project description:FABP4 Contributes to Preeclampsia Through Dysregulating Lipid Metabolism and Inducing Mitochondrial Oxidative Stress in Trophoblasts
| PRJNA1312857 | ENA
Project description:Preeclampsia (PE) is a pregnancy complication that seriously threatens maternal and fetal health, but its pathogenesis is unclear. A growing number of studies have revealed significant changes in the mitochondria of placental trophoblasts in PE, with abnormalities in mitochondrial content, morphology, and function, but the regulatory mechanisms are not clear. Siglec-6 belongs to the family of sialic acid-binding immunoglobulin-like lectins (Siglecs), and studies have demonstrated that the Siglecs family is capable of modulating the oxidative phosphorylation and energy metabolism of mitochondria. Our study revealed that Siglec-6, which is mainly localized in syncytiotrophoblasts (STB) and extravillous trophoblast (EVT), is abnormally up-regulated in EVT in early-onset PE (EO-PE). Siglec-6 inhibited trophoblast migration, invasion, and impaired mitochondrial function. Mechanistic studies revealed that Siglec-6 inhibits NF-κB activation by recruiting SHP1/SHP2, leading to an increase in GPR20 expression, which further suppresses the downstream c-AMP/PKA/ERK signaling pathway and causes mitochondrial dysfunction in trophoblast cells. Placenta-specific overexpression of Siglec-6 in an animal model causes impaired placental structure and vessel formation, leading to a PE-like phenotype in mice. We conclude that trophoblast upregulated Siglec-6 induced trophoblast mitochondrial dysfunction through the SHP1/SHP2-NF-κB-GPR20 signaling pathway, leading to diminished trophoblast migration, invasion, and ultimately mediating the development of PE. Our study provides new ideas for the pathogenesis of PE and may provide new targets for the prevention or treatment of PE.
2025-12-31 | GSE247109 | GEO
Project description:Oxidative stress plays a crucial role in preeclampsia (PE) pathogenesis. Evidence indicates altered microRNAs (miRNAs) expression in PE, however, the relationship between oxidative stress and miRNA changes in placenta as a potential mechanism involved in PE is not fully elucidated. In the present study, we investigate the impact of increased oxidative stress on miRNA and mRNA expression profiles of genes known to be associated with PE in villous 3A first trimester trophoblast cells. Cells were exposed to H2O2 at 10 different concentrations (0-1 mM) for 0.5, 4, 24, and 48 h. Cytotoxicity was determined using the SRB assay and data was used to calculate the IC50 of H2O2. Total RNA was extracted after short-term exposure (4 h) to H2O2 for miRNA expression profiling. H2O2 exerted a concentration and time-dependent cytotoxicity on 3A trophoblast cells. Short-term exposure of 3A cells to low concentration of H2O2 (5% of IC50) significantly altered miRNA profile as evidenced by significant changes in 195 out of 595 evaluatable miRNAs. Short-term exposure of villous first trimester trophoblasts to low concentrations of H2O2 significantly alters miRNA profile. Oxidative stress plays a crucial role in preeclampsia (PE) pathogenesis. Evidence indicates altered microRNAs (miRNAs) expression in PE, however, the relationship between oxidative stress and miRNA changes in placenta as a potential mechanism involved in PE is not fully elucidated. In the present study, we investigate the impact of increased oxidative stress on miRNA and mRNA expression profiles of genes known to be associated with PE in villous 3A first trimester trophoblast cells. Cells were exposed to H2O2 at 10 different concentrations (0-1 mM) for 0.5, 4, 24, and 48 h. Cytotoxicity was determined using the SRB assay and data was used to calculate the IC50 of H2O2. Total RNA was extracted after short-term exposure (4 h) to H2O2 for miRNA expression profiling. H2O2 exerted a concentration and time-dependent cytotoxicity on 3A trophoblast cells. Short-term exposure of 3A cells to low concentration of H2O2 (5% of IC50) significantly altered miRNA profile as evidenced by significant changes in 195 out of 595 evaluatable miRNAs. Short-term exposure of villous first trimester trophoblasts to low concentrations of H2O2 significantly alters miRNA profile.
2015-12-31 | GSE63999 | GEO
Project description:Oxidative stress plays a crucial role in preeclampsia (PE) pathogenesis. Evidence indicates altered microRNAs (miRNAs) expression in PE, however, the relationship between oxidative stress and miRNA changes in placenta as a potential mechanism involved in PE is not fully elucidated. In the present study, we investigate the impact of increased oxidative stress on miRNA and mRNA expression profiles of genes known to be associated with PE in villous 3A first trimester trophoblast cells. Cells were exposed to H2O2 at 10 different concentrations (0-1 mM) for 0.5, 4, 24, and 48 h. Cytotoxicity was determined using the SRB assay and data was used to calculate the IC50 of H2O2. Total RNA was extracted after short-term exposure (4 h) to H2O2 for miRNA expression profiling. H2O2 exerted a concentration and time-dependent cytotoxicity on 3A trophoblast cells. Short-term exposure of 3A cells to low concentration of H2O2 (5% of IC50) significantly altered miRNA profile as evidenced by significant changes in 195 out of 595 evaluatable miRNAs. Short-term exposure of villous first trimester trophoblasts to low concentrations of H2O2 significantly alters miRNA profile. Oxidative stress plays a crucial role in preeclampsia (PE) pathogenesis. Evidence indicates altered microRNAs (miRNAs) expression in PE, however, the relationship between oxidative stress and miRNA changes in placenta as a potential mechanism involved in PE is not fully elucidated. In the present study, we investigate the impact of increased oxidative stress on miRNA and mRNA expression profiles of genes known to be associated with PE in villous 3A first trimester trophoblast cells. Cells were exposed to H2O2 at 10 different concentrations (0-1 mM) for 0.5, 4, 24, and 48 h. Cytotoxicity was determined using the SRB assay and data was used to calculate the IC50 of H2O2. Total RNA was extracted after short-term exposure (4 h) to H2O2 for miRNA expression profiling. H2O2 exerted a concentration and time-dependent cytotoxicity on 3A trophoblast cells. Short-term exposure of 3A cells to low concentration of H2O2 (5% of IC50) significantly altered miRNA profile as evidenced by significant changes in 195 out of 595 evaluatable miRNAs. Short-term exposure of villous first trimester trophoblasts to low concentrations of H2O2 significantly alters miRNA profile. Cells were grown to 90% confluency in 75 cm2 flasks and exposed to 25 µM H2O2 in complete medium for 4 h. Total RNA was isolated using the Qiagen miRNEasy Mini Kit and quality/quantity measured in the Molecular Genomics Core at UTMB. RNA was quantitated spectrophotometrically using a NanoDrop ND-1000 (NanoDrop Techniologies, DE). Quality of the purified RNA was assessed by visualization of 18S and 28S RNA bands using an Agilent BioAnalyzer 2100 (Agilent Technologies, CA). Resulting electroperograms were used in the calculation of the 28S/18S ratio and the RNA Integrity Number. Reverse transcription was carried out using either the miScript II RT kit or RT2 First Strand and subsequent SYBR green based real-time PCR on a BioRad Chromo4 Real-Time PCR Detector per manufacturerâs recommendation. The miRNA profile screening was performed using miScript Human miRNome PCR Array (MIHS-3216Z, Qiagen, Valencia, CA). Data was analyzed using the ÎÎCT method with the miScript miRNA PCR Array Data Analysis version 3.5 (SABiosciences, Valencia CA).
2015-12-31 | E-GEOD-63999 | biostudies-arrayexpress
Project description:Preeclampsia(PE)is a severe placental disorder that affects 3%-5% of all pregnancies worldwide. The primary cause of PE is abnormal placentationduring eanly pregnancy, including poor trophoblast invasion and insutficientapiral arteriole remodeling, Protein O-ucosylation is a type of protein posttranslational modification that is catalyzed by Protein O-fucosy'ltransferase(poFUT). However, the role and underlying mechanisms of protein O-fucosylation and poFUT1 in PE remain elusive.
2025-12-25 | PXD072416 |
Project description:Fatty acid binding protein 4 (FABP4) is known to play important roles in lipid metabolism in multple cell types including in macrophages. In the present study, we used single cell RNA-sequencing in macrophages extracted from either wild-type or mice deficient in FABP4 to further explore the pathways downstream of FABP4 in splenic macrophages.
2025-03-21 | GSE262196 | GEO
Project description:Preeclampsia, a life threatening hypertensive disorder of pregnancy, is a leading cause of maternal and perinatal morbidity and mortality. Its early onset form (EO PE), requiring delivery before 34 weeks of gestation, is particularly severe and closely linked to defective trophoblast differentiation. Here, we identify BRCA1-associated protein 1 (BAP1) and its cofactors ASXL2 and ASXL3 are upregulated in EO PE placentas. Enforced BAP1 expression in human trophoblast stem cells reinforced epithelial identity, enhanced adhesion, and impaired both extravillous trophoblast differentiation and syncytiotrophoblast formation. Integrated transcriptomic and proteomic analyses revealed suppression of lineage-specific pathways alongside maintenance of progenitor-like and pro-inflammatory signatures. In trophoblast organoids, excess of BAP1 disrupted syncytial maturation and induced interferon-driven pathways overlapping with EO PE transcriptomes. Together, these findings establish BAP1 as a key regulator of human trophoblast differentiation and implicate its dysregulation in the pathogenesis of EO PE, providing mechanistic insight into the cellular basis of placental dysfunction.
2026-03-27 | GSE311483 | GEO
Project description:Introduction: Aging is characterized by progressive metabolic dyshomeostasis that increases morbidity and mortality. Solutions for optimizing healthy aging are challenged by lacking appropriate biomarkers. Moreover, druggable targets to rejuvenate the aging-associated metabolic phenotypes remain unavailable. Methods: Proteomics analysis was performed in a cohort of young and elderly adults. Circulating levels of insulin-like growth factor 1 (IGF-1) and fatty acid binding protein 4 (FABP4) were evaluated by ELISA. FABP4 was silenced in elderly mice by adeno-associated virus. Metabolic activities were measured by metabolic cages. Cognitive function was evaluated by Morris water maze. Glucose and lipid metabolism were evaluated by biochemistry assays with blood samples. RNA-seq in mouse liver was performed for transcriptome analysis. Results: Among 9 aging-sensitive proteins shared by both male and female, FABP4 was identified as a reliable aging biomarker in both human and mouse. Silencing FABP4 in elderly mice significantly rejuvenated the aging-associated decline in metabolic activities. FABP4 knockdown reversed the aging-associated metabolic disorders by promoting degradation of cholesterol and fatty acids, while suppressing gluconeogenesis. Transcriptome analysis revealed a restoration of the pro-aging gene reprogramming towards inflammation and metabolic disorders in the liver after FABP4 knockdown. FABP4 overexpression promoted human LO2 cell senescence. Moreover, administration of an FABP4 inhibitor BMS309403 delivered metabolic benefits in elderly mice. Conclusion: Our findings demonstrate FABP4 as a reliable aging biomarker as well as a practicable target to improve healthy aging in the elderly. Keywords: Aging; Biomarkers; FABP4; Metabolic disorders; Rejuvenation; Senescence.
2025-10-13 | GSE215378 | GEO
Project description:Fatty acid-binding protein 4 (FABP4), a key lipid protein in metabolism and inflammation, has been suggested to be linked to osteoporosis (OP), though direct evidence is scarce. Here, we present the first clear evidence of FABP4's significant role in OP, supported by clinical data and comprehensive in vivo and in vitro experiments. Elevated serum FABP4 in OP patients inversely correlates with bone mineral density (BMD), with similar trends observed in OVX mice. While FABP4 does not influence osteoblast differentiation, it promotes osteoclast formation and bone resorption. The FABP4 inhibitor BMS309403, with an IC50 of 0.89 μM, inhibits osteoclast differentiation by modulating calcium ions and suppressing the Ca2+-Calcineurin-NFATc pathway. Oral BMS309403 increased BMD in OVX mice, albeit less effectively than alendronate, whereas bone-targeted PLGA nanoparticles showed comparable efficacy to alendronate. This research identifies FABP4 as a promising therapeutic target for OP, with significant clinical implications.
2025-04-09 | GSE273951 | GEO
Project description:Preeclampsia (PE) is the leading cause of prenatal morbidity and mortality. It is associated with defective trophoblast functions at implantation, but manifestation of its phenotypes is in late pregnancy. There is no reliable method for early prediction and treatment of PE. Adrenomedullin (ADM) is an abundant placental peptide in early pregnancy. Here, integrated single-cell sequencing and spatial transcriptomics confirm a high ADM expression in the human villous cytotrophoblast. The levels of ADM in chorionic villi and serum were lower in first-trimester pregnant women who later developed PE than those with normotensive pregnancy. ADM stimulates differentiation of trophoblast stem cells and trophoblast organoids in vitro. In pregnant mice, placenta-specific ADM suppression led to PE-like phenotypes. The PE-like phenotypes in a mouse PE model were reduced by a novel placenta-specific nanoparticle-based forced expression of ADM. Our study reveals the roles of trophoblastic ADM in placental development, PE pathogenesis and its potential clinical uses.
2023-07-09 | GSE236475 | GEO