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PPAR Research 2024We have previously reported the identification of a novel splicing variant of the mouse peroxisome proliferator-activated receptor- (), referred to as . This variant,...
We have previously reported the identification of a novel splicing variant of the mouse peroxisome proliferator-activated receptor- (), referred to as . This variant, encoding the PPAR1 protein, is abundantly and ubiquitously expressed, playing a crucial role in adipogenesis. possesses a unique promoter and 5' untranslated region (5'UTR), distinct from those of the canonical mouse and mRNAs. We observed a significant increase in DNA methylation at two CpG sites within the proximal promoter region (-733 to -76) of during adipocyte differentiation. Concurrently, chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) using antibodies against H3K4me3 and H3K27ac indicated marked elevations in both methylation and acetylation of histone H3, while the repressive histone mark H3K9me2 significantly decreased, at the transcription start sites of both and following differentiation. Knocking down using specific siRNA also led to a decrease in mRNA and PPAR2 protein levels; conversely, knocking down resulted in reduced mRNA and PPAR1 protein levels, suggesting synergistic transcriptional regulation of and during adipogenesis. Furthermore, our experiments utilizing the CRISPR-Cas9 system identified crucial PPAR-binding sites within the gene locus, underscoring their significance in adipogenesis. Based on these findings, we propose a model of positive feedback regulation for and expression during the adipocyte differentiation process in 3T3-L1 cells.
PubMed: 38899160
DOI: 10.1155/2024/5518933 -
Physiological Reports Jun 2024This study aimed to investigate how intermittent hyperoxic exposure (three cycles of 21% O [10 min] and 30% O [15 min]) affects exercise performance in mice. Three...
This study aimed to investigate how intermittent hyperoxic exposure (three cycles of 21% O [10 min] and 30% O [15 min]) affects exercise performance in mice. Three hours after the acute exposure, there was an observed increase in mRNA levels of phosphofructokinase (Bayes factor [BF] ≥ 10), mitochondrial transcription factor-A (BF ≥10), PPAR-α (BF ≥3), and PPAR-γ (BF ≥3) in the red gastrocnemius muscle (Gr). Four weeks of exercise training under intermittent (INT), but not continuous (HYP), hyperoxia significantly (BF ≥30) increased maximal exercise capacity compared to normoxic exercise-trained (ET) group. INT group exhibited significantly higher activity levels of 3-hydroxyacyl-CoA-dehydrogenase (HAD) in Gr (BF = 7.9) compared to ET group. Pyruvate dehydrogenase complex activity levels were significantly higher in INT group compared to ET group in white gastrocnemius, diaphragm, and left ventricle (BF ≥3). NT-PGC1α protein levels in Gr (BF = 7.7) and HAD activity levels in Gr (BF = 6.9) and soleus muscles (BF = 3.3) showed a significant positive correlation with maximal work values. These findings suggest that exercise training under intermittent hyperoxia is a beneficial strategy for enhancing endurance performance by improving fatty acid and pyruvic acid utilization.
Topics: Animals; Male; Muscle, Skeletal; Mice; Physical Conditioning, Animal; Physical Endurance; Mice, Inbred C57BL; Hyperoxia; PPAR alpha; PPAR gamma; Phosphofructokinases; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Transcription Factors; DNA-Binding Proteins; Mitochondrial Proteins
PubMed: 38898524
DOI: 10.14814/phy2.16117 -
BioRxiv : the Preprint Server For... Jun 2024Angiopoietin-like 3 (ANGPTL3) is a key regulator of lipoprotein metabolism, known for its potent inhibition on intravascular lipoprotein and endothelial lipase...
Angiopoietin-like 3 (ANGPTL3) is a key regulator of lipoprotein metabolism, known for its potent inhibition on intravascular lipoprotein and endothelial lipase activities. Recent studies have shed light on the cellular functions of ANGPTL3. However, the precise mechanism underlying its regulation of cellular lipid metabolism remains elusive. We recently reported that ANGPTL3 interacts with the chromatin regulator SMARCAL1, which plays a pivotal role in maintaining cellular lipid homeostasis. Here, through a combination of in vitro and in vivo functional analyses, we provide evidence that ANGPTL3 indeed influences cellular lipid metabolism. Increased expression of Angptl3 prompted the formation of lipid droplets (LDs) in response to slow growth conditions. Notably, under the conditions, Angptl3 accumulated within cytoplasmic peroxisomes, where it interacts with SmarcAL1, which translocated from nucleus as observed previously. This translocation induced changes in gene expression favoring triglyceride (TG) accumulation. Indeed, gene knockout (KO) in human cells increased the expression of key lipid genes, which could be linked to elevated nuclear localization of SMARCAL1, whereas the expression of these genes decreased in KO cells. Consistent with these findings, the injection of Angptl3 protein to mice led to hepatic fat accumulation derived from circulating blood, a phenotype likely indicative of its long-term effect on blood TG, linked to SmarcAL1 activities. Thus, our results suggest that the Angptl3-SmarcAL1 pathway may confer the capacity for TG storage in cells in response to varying growth states, which may have broad implications for this pathway in regulating energy storage and trafficking.
PubMed: 38895318
DOI: 10.1101/2024.06.03.597253 -
Nutrients May 2024This study examined whey protein's impact on insulin resistance in a high-fat diet-induced pediatric obesity mouse model. Pregnant mice were fed high-fat diets, and male...
This study examined whey protein's impact on insulin resistance in a high-fat diet-induced pediatric obesity mouse model. Pregnant mice were fed high-fat diets, and male pups continued this diet until 8 weeks old, then were split into high-fat, whey, and casein diet groups. At 12 weeks old, their body weight, fasting blood glucose (FBG), blood insulin level (IRI), homeostatic model assessment for insulin resistance (HOMA-IR), liver lipid metabolism gene expression, and liver metabolites were compared. The whey group showed significantly lower body weight than the casein group at 12 weeks old ( = 0.034). FBG was lower in the whey group compared to the high-fat diet group ( < 0.01) and casein group ( = 0.058); IRI and HOMA-IR were reduced in the whey group compared to the casein group ( = 0.02, < 0.01, < 0.01, respectively). The levels of peroxisome proliferator-activated receptor α and hormone-sensitive lipase were upregulated in the whey group compared to the casein group ( < 0.01, = 0.03). Metabolomic analysis revealed that the levels of taurine and glycine, both known for their anti-inflammatory and antioxidant properties, were upregulated in the whey group in the liver tissue ( < 0.01, < 0.01). The intake of whey protein was found to improve insulin resistance in a high-fat diet-induced pediatric obesity mouse model.
Topics: Animals; Whey Proteins; Insulin Resistance; Diet, High-Fat; Male; Mice; Disease Models, Animal; Pediatric Obesity; Liver; Female; Blood Glucose; Insulin; Lipid Metabolism; Pregnancy; Mice, Inbred C57BL
PubMed: 38892554
DOI: 10.3390/nu16111622 -
International Journal of Molecular... May 2024Thaumatin-like proteins (TLPs) in plants are involved in diverse biotic and abiotic stresses, including antifungal activity, low temperature, drought, and high salinity....
Thaumatin-like proteins (TLPs) in plants are involved in diverse biotic and abiotic stresses, including antifungal activity, low temperature, drought, and high salinity. However, the roles of the genes are rarely reported in early flowering. Here, the gene family was identified in . The 49 genes were classified into 10 clusters, and gene structures, conserved motifs, and expression patterns were analyzed in these genes. Among 49 genes, the transcription level is preferentially high in stems, and GUS staining signals were mainly detected in the phloem tissues of the pro::GUS transgenic poplars. We generated transgenic plants overexpressing the gene, and its overexpression lines showed early flowering phenotypes. However, the expression levels of main flowering regulating genes were not significantly altered in these -overexpressing plants. Our data further showed that overexpression of the gene led to a reactive oxygen species (ROS) burst in , which might advance the development process of transgenic plants. In addition, subcellular localization of -fused green fluorescent protein (GFP) was in peroxisome, as suggested by tobacco leaf transient transformation. Overall, this work provides a comprehensive analysis of the gene family in and an insight into the role of TLPs in woody plants.
Topics: Populus; Plant Proteins; Phloem; Gene Expression Regulation, Plant; Arabidopsis; Plants, Genetically Modified; Multigene Family; Phylogeny; Reactive Oxygen Species; Flowers; Genome, Plant
PubMed: 38892187
DOI: 10.3390/ijms25115990 -
Cells Jun 2024Precise control of neuronal activity is crucial for the proper functioning of neurons. How lipid homeostasis contributes to neuronal activity and how much of it is...
Precise control of neuronal activity is crucial for the proper functioning of neurons. How lipid homeostasis contributes to neuronal activity and how much of it is regulated by cells autonomously is unclear. In this study, we discovered that absence of the lipid regulator , a functional ortholog of the peroxisome proliferator-activated receptor (PPAR) in , resulted in defective pathogen avoidance behavior against (PA14). Functional NHR-49 was required in the neurons, and more specifically, in a set of oxygen-sensing body cavity neurons, URX, AQR, and PQR. We found that lowering the neuronal activity of the body cavity neurons improved avoidance in mutants. Calcium imaging in URX neurons showed that mutants displayed longer-lasting calcium transients in response to an O upshift, suggesting that excess neuronal activity leads to avoidance defects. Cell-specific rescue of NHR-49 in the body cavity neurons was sufficient to improve pathogen avoidance, as well as URX neuron calcium kinetics. Supplementation with oleic acid also improved avoidance behavior and URX calcium kinetics, suggesting that the defective calcium response in the neuron is due to lipid dysfunction. These findings highlight the role of cell-autonomous lipid regulation in neuronal physiology and immune behavior.
Topics: Animals; Caenorhabditis elegans; Lipid Metabolism; Caenorhabditis elegans Proteins; Neurons; Pseudomonas aeruginosa; Calcium; Mutation; Avoidance Learning; Receptors, Cytoplasmic and Nuclear
PubMed: 38891110
DOI: 10.3390/cells13110978 -
Cells May 2024This study explores the impact of environmental pollutants on nuclear receptors (CAR, PXR, PPARα, PPARγ, FXR, and LXR) and their heterodimerization partner, the...
This study explores the impact of environmental pollutants on nuclear receptors (CAR, PXR, PPARα, PPARγ, FXR, and LXR) and their heterodimerization partner, the Retinoid X Receptor (RXR). Such interaction may contribute to the onset of non-alcoholic fatty liver disease (NAFLD), which is initially characterized by steatosis and potentially progresses to steatohepatitis and fibrosis. Epidemiological studies have linked NAFLD occurrence to the exposure to environmental contaminants like PFAS. This study aims to assess the simultaneous activation of nuclear receptors via perfluorooctanoic acid (PFOA) and RXR coactivation via Tributyltin (TBT), examining their combined effects on steatogenic mechanisms. Mice were exposed to PFOA (10 mg/kg/day), TBT (5 mg/kg/day) or a combination of them for three days. Mechanisms underlying hepatic steatosis were explored by measuring nuclear receptor target gene and lipid metabolism key gene expressions, by quantifying plasma lipids and hepatic damage markers. This study elucidated the involvement of the Liver X Receptor (LXR) in the combined effect on steatosis and highlighted the permissive nature of the LXR/RXR heterodimer. Antagonistic effects of TBT on the PFOA-induced activation of the Pregnane X Receptor (PXR) and Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) were also observed. Overall, this study revealed complex interactions between PFOA and TBT, shedding light on their combined impact on liver health.
Topics: Animals; Trialkyltin Compounds; Caprylates; Mice; Fluorocarbons; Male; Mice, Inbred C57BL; Liver X Receptors; Liver; Retinoid X Receptors; Fatty Liver; Receptors, Cytoplasmic and Nuclear; Lipid Metabolism; Non-alcoholic Fatty Liver Disease
PubMed: 38891072
DOI: 10.3390/cells13110940 -
Journal of Thoracic Disease May 2024Chronic obstructive pulmonary disease (COPD) is significantly influenced by oxidative stress. Recent studies have elucidated the anti-oxidative stress properties of...
BACKGROUND
Chronic obstructive pulmonary disease (COPD) is significantly influenced by oxidative stress. Recent studies have elucidated the anti-oxidative stress properties of peroxisome proliferator-activated receptors γ (PPARγ), augmenting its known anti-inflammatory effects. The exact influence of PPARγ on oxidative stress in COPD remains elusive. This study aimed to investigate the potential mechanism by which PPARγ counteracts the oxidative stress instigated by cigarette smoke in macrophages.
METHODS
Macrophages were cultured and exposed to 1% cigarette smoke extract (CSE), 1 µg/mL erythromycin (EM), and 10 µmol/mL GW9662 (a PPARγ antagonist). Reactive oxygen species (ROS) in macrophages was identified using fluorescent microscopy. PPARγ expression was ascertained through reverse transcription-polymerase chain reaction (RT-PCR) and Western blot techniques. The superoxide dismutase (SOD) in macrophage supernatant was measured by enzyme linked immunosorbent assay (ELISA), as was malondialdehyde (MDA).
RESULTS
Our results shown that cigarette smoke stimulated macrophages to increase ROS release, decrease the expression of PPARγ, increase the expression of MDA and decrease the expression of SOD. After PPARγ inhibitor acted on macrophages stimulated by cigarette smoke, the expression of MDA was inhibited and the content of SOD increased. When EM was used to treat macrophages stimulated by cigarette smoke, the expression of ROS decreased, the expression of PPARγ increased, the expression of MDA decreased and the expression of SOD increased.
CONCLUSIONS
This study suggests that PPARγ plays an anti-oxidative role by inhibiting the expression of MDA and promoting the expression of SOD. Cigarette smoke induces oxidative stress by inhibiting PPARγ pathway. EM inhibits oxidative stress by activating PPARγ pathway.
PubMed: 38883674
DOI: 10.21037/jtd-23-1647 -
Frontiers in Endocrinology 2024Diabetes mellitus is an independent risk factor for heart failure, and diabetes-induced heart failure severely affects patients' health and quality of life. Cuproptosis...
Potential molecular and cellular mechanisms of the effects of cuproptosis-related genes in the cardiomyocytes of patients with diabetic heart failure: a bioinformatics analysis.
BACKGROUND
Diabetes mellitus is an independent risk factor for heart failure, and diabetes-induced heart failure severely affects patients' health and quality of life. Cuproptosis is a newly defined type of programmed cell death that is thought to be involved in the pathogenesis and progression of cardiovascular disease, but the molecular mechanisms involved are not well understood. Therefore, we aimed to identify biomarkers associated with cuproptosis in diabetes mellitus-associated heart failure and the potential pathological mechanisms in cardiomyocytes.
MATERIALS
Cuproptosis-associated genes were identified from the previous publication. The GSE26887 dataset was downloaded from the GEO database.
METHODS
The consistency clustering was performed according to the cuproptosis gene expression. Differentially expressed genes were identified using the limma package, key genes were identified using the weighted gene co-expression network analysis(WGCNA) method, and these were subjected to immune infiltration analysis, enrichment analysis, and prediction of the key associated transcription factors. Consistency clustering identified three cuproptosis clusters. The differentially expressed genes for each were identified using limma and the most critical MEantiquewhite4 module was obtained using WGCNA. We then evaluated the intersection of the MEantiquewhite4 output with the three clusters, and obtained the key genes.
RESULTS
There were four key genes: , , , and . , , and were negatively associated with multiple immune factors, while was positively associated, and T-cells accounted for a major proportion of this relationship with the immune system. Four enriched pathways were found to be associated: arachidonic acid metabolism, peroxisomes, fatty acid metabolism, and dorsoventral axis formation, which may be regulated by the transcription factor MECOM, through a change in protein structure.
CONCLUSION
HSDL2, BCO2, CORIN, and SNORA80E may regulate cardiomyocyte cuproptosis in patients with diabetes mellitus-associated heart failure through effects on the immune system. The product of the cuproptosis-associated gene is probably involved in myocardial fibrosis in patients with diabetes, which leads to the development of cardiac insufficiency.
Topics: Myocytes, Cardiac; Humans; Heart Failure; Computational Biology; Gene Expression Profiling; Gene Regulatory Networks; Ferroptosis; Diabetic Cardiomyopathies
PubMed: 38883603
DOI: 10.3389/fendo.2024.1370387 -
Cureus May 2024Tenosynovial giant cell tumor (TGCT) is a monoarticular fibrohistiocytic benign or locally aggressive soft tissue tumor that originates from the synovium of joints,...
BACKGROUND
Tenosynovial giant cell tumor (TGCT) is a monoarticular fibrohistiocytic benign or locally aggressive soft tissue tumor that originates from the synovium of joints, bursae, and tendon sheaths. It has an inflammatory neoplastic nature, with a clinical presentation ranging from pain, swelling, stiffness, and limited range of movement to joint instability and blockage. Its uncommon incidence leads to a poorly understood pathogenesis. Localized forms of TGCT (LTGCT) can cause significant morbidity, interfere with daily patient activities, and decrease the patient's quality of life in challenging cases. This study aimed to investigate the immunohistochemical expression of PPARγ (peroxisome proliferator-activated receptor gamma) and P53 in LTGCT to understand the disease better and offer potential therapeutic targets.
METHODS
The study is cross-sectional, in which 27 LTGCT cases were collected from the Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt. Solitary and multiple LTGCT cases retrieved between January 2018 and December 2022 were included, and immunohistochemically stained with anti-PPARγ and P53 antibodies. The TGCT samples were excluded if they were insufficient for sectioning, processing, and interpretation, over-fixed, had process artifacts, or were of the diffuse TGCT type. Scoring of stain expression was performed by ImageJ (National Institutes of Health, Bethesda, MD) analysis using the threshold method and was expressed in percent area/high power field. Clinicopathological correlations were analyzed.
RESULTS
All the 27 collected LTGCT cases were located in the small joints of patients' hands. Cases with solitary LGTCTs constituted 55.6% (n = 15), while 44.4% (n = 12) had multiple LTGCTs related to one affected site/case (e.g., multiple tumors in one finger). PPARγ was expressed in the cytoplasm of mononuclear and multinucleated tumor cells and foamy histiocytes, while P53 expression was mainly in mononuclear cells' nuclei. PPARγ significantly correlated with P53 expression (r = 0.9 and P = 0.000). PPARγ (r = 0.4 and P = 0.02) and P53 (r = 0.5 and P = 0.01) were positively correlated with tumor size. Only P53 expression was positively correlated with tumor multiplicity (r = 0.4 and P = 0.03). Using the receiver operating characteristic curve test, the P53 cutoff score detecting the multiplicity of TGCTs was ≥20.5%, with a 75% sensitivity and 80% specificity.
CONCLUSION
PPARγ and P53 have a significant role in LTGCT growth, while P53 plays a role in tumor multiplicity. They can be possible targets in LTGCTs unfit for excision.
PubMed: 38882990
DOI: 10.7759/cureus.60377