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Poultry Science Dec 2020Peroxisome proliferator-activated receptor γ (PPARγ) has 2 protein isoforms (PPARγ1 and PPARγ2) generated by alternative promoter usage and alternative splicing....
Peroxisome proliferator-activated receptor γ (PPARγ) has 2 protein isoforms (PPARγ1 and PPARγ2) generated by alternative promoter usage and alternative splicing. However, their functional uniqueness and similarity remain unclear. In the study, we investigated the effects of lentivirus-mediated overexpression of PPARγ1 and PPARγ2 on proliferation, apoptosis, and differentiation of the immortalized chicken preadipocytes. Cell Counting Kit-8 assay showed PPARγ1 and PPARγ2 overexpression markedly suppressed cell proliferation, and fluorescence activated cell sorting analysis showed that PPARγ1 and PPARγ2 overexpression caused cell cycle arrest at G0/G1 phase. Cell death detection ELISA analysis showed both PPARγ1 and PPARγ2 overexpression induced cell apoptosis. Oil red O staining and gene expression analysis showed both PPARγ1 and PPARγ2 overexpression promoted preadipocyte differentiation. In the presence of PPARγ ligand, rosiglitazone, PPARγ2 overexpression was more potent in inducing apoptosis, promoting adipogenesis, and suppressing cell proliferation than PPARγ1 overexpression. We further explored the molecular basis for their functional differences. Reporter gene assay showed that under ligand conditions, PPARγ2 overexpression resulted in 1.68-fold increase in transcription activity compared with PPARγ1. Electrophoretic mobility shift assay showed both PPARγ1 and PPARγ2 could bind to PPAR response element (PPRE) as heterodimer with retinoid X receptor alpha, and by comparison, PPARγ2 had a higher affinity for PPRE than PPARγ1. Reporter gene assay showed expression PPARγ1 and PPARγ2 similarly induced fatty acid synthase and adipocyte fatty acid-binding protein promoter activity but differentially induced lipoprotein lipase and perilipin 1 promoter activities. Coimmunoprecipitation analysis showed that PPARγ1 and PPARγ2 interacted similarly with the coactivators, Tat-interacting protein 60. Taken together, our results demonstrate that PPARγ1 and PPARγ2 differentially regulate preadipocyte proliferation, apoptosis, and differentiation as a result of their distinct and overlapping molecular functions.
Topics: Adipocytes; Animals; Apoptosis; Cell Differentiation; Cell Proliferation; Chickens; PPAR gamma; Protein Isoforms
PubMed: 33248556
DOI: 10.1016/j.psj.2020.09.086 -
International Journal of Molecular... Jul 2018Peroxisome proliferator-activated receptors (PPARs) are a well-known pharmacological target for the treatment of multiple diseases, including diabetes mellitus,... (Review)
Review
Peroxisome proliferator-activated receptors (PPARs) are a well-known pharmacological target for the treatment of multiple diseases, including diabetes mellitus, dyslipidemia, cardiovascular diseases and even primary biliary cholangitis, gout, cancer, Alzheimer's disease and ulcerative colitis. The three PPAR isoforms (α, β/δ and γ) have emerged as integrators of glucose and lipid metabolic signaling networks. Typically, PPARα is activated by fibrates, which are commonly used therapeutic agents in the treatment of dyslipidemia. The pharmacological activators of PPARγ include thiazolidinediones (TZDs), which are insulin sensitizers used in the treatment of type 2 diabetes mellitus (T2DM), despite some drawbacks. In this review, we summarize 84 types of PPAR synthetic ligands introduced to date for the treatment of metabolic and other diseases and provide a comprehensive analysis of the current applications and problems of these ligands in clinical drug discovery and development.
Topics: Animals; Anti-Inflammatory Agents; Disease Models, Animal; Drug Discovery; Humans; Hypolipidemic Agents; Ligands; Metabolic Diseases; Mice; Molecular Conformation; Molecular Targeted Therapy; Peroxisome Proliferator-Activated Receptors; Protein Isoforms; Rats
PubMed: 30060458
DOI: 10.3390/ijms19082189 -
International Journal of Molecular... Mar 2023Benign prostatic hyperplasia (BPH) is a common disease in elderly men with an uncertain etiology and mechanistic basis. Metabolic syndrome (MetS) is also a very common...
Benign prostatic hyperplasia (BPH) is a common disease in elderly men with an uncertain etiology and mechanistic basis. Metabolic syndrome (MetS) is also a very common illness and is closely related to BPH. Simvastatin (SV) is one of the widely used statins for MetS. Peroxisome-proliferator-activated receptor gamma (PPARγ), crosstalking with the WNT/β-catenin pathway, plays important roles in MetS. Our current study aimed to examine SV-PPARγ-WNT/β-catenin signaling in the development of BPH. Human prostate tissues and cell lines plus a BPH rat model were utilized. Immunohistochemical, immunofluorescence, hematoxylin and eosin (H&E) and Masson's trichrome staining, construction of a tissue microarray (TMA), ELISA, CCK-8 assay, qRT-PCR, flow cytometry, and Western blotting were also performed. PPARγ was expressed in both prostate stroma and epithelial compartments and downregulated in BPH tissues. Furthermore, SV dose-dependently triggered cell apoptosis and cell cycle arrest at the G0/G1 phase and attenuated tissue fibrosis and the epithelial-mesenchymal transition (EMT) process both in vitro and in vivo. SV also upregulated the PPARγ pathway, whose antagonist could reverse SV produced in the aforementioned biological process. Additionally, crosstalk between PPARγ and WNT/β-catenin signaling was demonstrated. Finally, correlation analysis with our TMA containing 104 BPH specimens showed that PPARγ was negatively related with prostate volume (PV) and free prostate-specific antigen (fPSA) and positively correlated with maximum urinary flow rate (Qmax). WNT-1 and β-catenin were positively related with International Prostate Symptom Score (IPSS) and nocturia, respectively. Our novel data demonstrate that SV could modulate cell proliferation, apoptosis, tissue fibrosis, and the EMT process in the prostate through crosstalk between PPARγ and WNT/β-catenin pathways.
Topics: Male; Humans; Rats; Animals; Aged; Prostatic Hyperplasia; PPAR gamma; beta Catenin; Simvastatin; Peroxisomes; Wnt Signaling Pathway; Cell Proliferation; Fibrosis
PubMed: 36902342
DOI: 10.3390/ijms24054911 -
PloS One 2015We previously found that peroxisomal biogenesis factor 11a (Pex11a) deficiency is associated with a reduction in peroxisome abundance and impaired fatty acid metabolism...
We previously found that peroxisomal biogenesis factor 11a (Pex11a) deficiency is associated with a reduction in peroxisome abundance and impaired fatty acid metabolism in hepatocytes, and results in steatosis. In the present study, we investigated whether butyrate induces Pex11a expression and peroxisome proliferation, and studied its effect on lipid metabolism. C57BL/6 mice fed standard chow or a high-fat diet (HFD) were treated with tributyrin, 4-phelybutyrate acid (4-PBA), or the butyrate-producing probiotics (Clostridium butyricum MIYAIRI 588 [CBM]) plus inulin (dietary fiber), and the body weight, white adipose tissue, serum triglycerides, mRNA expression, and peroxisome abundance were evaluated. Tributyrin or 4-PBA treatment significantly decreased body weight and increased hepatic mRNA expression of peroxisome proliferator-activated receptor-α (PPARα) and Pex11a. In addition, 4-PBA treatment increased peroxisome abundance and the expression of genes involved in peroxisomal fatty acid β-oxidation (acyl-coenzyme A oxidase 1 and hydroxysteroid [17-beta] dehydrogenase 4). CBM and inulin administration reduced adipose tissue mass and serum triglycerides, induced Pex11a, acyl-coenzyme A oxidase 1, and hydroxysteroid (17-beta) dehydrogenase 4 genes, and increased peroxisome abundance in mice fed standard chow or an HFD. In conclusion, elevation of butyrate availability (directly through administration of butyrate or indirectly via administration of butyrate-producing probiotics plus fiber) induces PPARα and Pex11a and the genes involved in peroxisomal fatty acid β-oxidation, increases peroxisome abundance, and improves lipid metabolism. These results may provide a new therapeutic strategy against hyperlipidemia and obesity.
Topics: Animals; Butyrates; Clostridium butyricum; Dietary Supplements; Gene Expression Regulation; Inulin; Male; Membrane Proteins; Mice; PPAR alpha; Peroxisomes; Probiotics
PubMed: 25659146
DOI: 10.1371/journal.pone.0117851 -
Seminars in Nephrology Mar 2018Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a key transcriptional regulator of mitochondrial biogenesis and function. Several recent... (Review)
Review
Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a key transcriptional regulator of mitochondrial biogenesis and function. Several recent studies have evaluated the role of PGC-1α in various renal cell types in healthy and disease conditions. Renal tubule cells mostly depend on mitochondrial fatty acid oxidation for energy generation. A decrease in PGC-1α expression and fatty acid oxidation is commonly observed in patient samples and mouse models with acute and chronic kidney disease. Conversely, increasing PGC-1α expression in renal tubule cells restores energy deficit and has been shown to protect from acute and chronic kidney disease. Other kidney cells, such as podocytes and endothelial cells, are less metabolically active and have a narrow PGC-1α tolerance. Increasing PGC-1α levels in podocytes induces podocyte proliferation and collapsing glomerulopathy development, while increasing PGC1-α in endothelial cells alters endothelial function and causes microangiopathy, thus highlighting the cell-type-specific role of PGC-1α in different kidney cells.
Topics: Acute Kidney Injury; Animals; Endothelial Cells; Epithelial Cells; Fibrosis; Gene Expression Regulation; Glomerulonephritis; Humans; Kidney; Kidney Tubules; Mitochondria; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Podocytes; Renal Insufficiency, Chronic
PubMed: 29602395
DOI: 10.1016/j.semnephrol.2018.01.003 -
MBio Aug 2023Peroxisomes are versatile eukaryotic organelles essential for many functions in fungi, including fatty acid metabolism, reactive oxygen species detoxification, and...
Peroxisomes are versatile eukaryotic organelles essential for many functions in fungi, including fatty acid metabolism, reactive oxygen species detoxification, and secondary metabolite biosynthesis. A suite of Pex proteins (peroxins) maintains peroxisomes, while peroxisomal matrix enzymes execute peroxisome functions. Insertional mutagenesis identified peroxin genes as essential components supporting the intraphagosomal growth of the fungal pathogen . Disruption of the peroxins Pex5, Pex10, or Pex33 in prevented peroxisome import of proteins targeted to the organelle via the PTS1 pathway. This loss of peroxisome protein import limited intracellular growth in macrophages and attenuated virulence in an acute histoplasmosis infection model. Interruption of the alternate PTS2 import pathway also attenuated virulence, although only at later time points of infection. The Sid1 and Sid3 siderophore biosynthesis proteins contain a PTS1 peroxisome import signal and localize to the peroxisome. Loss of either the PTS1 or PTS2 peroxisome import pathway impaired siderophore production and iron acquisition in , demonstrating compartmentalization of at least some biosynthetic steps for hydroxamate siderophore biosynthesis. However, the loss of PTS1-based peroxisome import caused earlier virulence attenuation than either the loss of PTS2-based protein import or the loss of siderophore biosynthesis, indicating additional PTS1-dependent peroxisomal functions are important for virulence. Furthermore, disruption of the Pex11 peroxin also attenuated virulence independently of peroxisomal protein import and siderophore biosynthesis. These findings demonstrate peroxisomes contribute to pathogenesis by facilitating siderophore biosynthesis and another unidentified role(s) for the organelle during fungal virulence. IMPORTANCE The fungal pathogen infects host phagocytes and establishes a replication-permissive niche within the cells. To do so, overcomes and subverts antifungal defense mechanisms which include the limitation of essential micronutrients. replication within host cells requires multiple distinct functions of the fungal peroxisome organelle. These peroxisomal functions contribute to pathogenesis at different times during infection and include peroxisome-dependent biosynthesis of iron-scavenging siderophores to enable fungal proliferation, particularly after activation of cell-mediated immunity. The multiple essential roles of fungal peroxisomes reveal this organelle as a potential but untapped target for the development of therapeutics.
Topics: Histoplasma; Virulence; Siderophores; Peroxins; Peroxisomes; Adaptation, Physiological
PubMed: 37432032
DOI: 10.1128/mbio.03284-22 -
International Journal of Molecular... Oct 2022Fusarium crown rot (FCR) of wheat, an important soil-borne disease, presents a worsening trend year by year, posing a significant threat to wheat production. cv. b was...
Fusarium crown rot (FCR) of wheat, an important soil-borne disease, presents a worsening trend year by year, posing a significant threat to wheat production. cv. b was reported to be the dominant pathogen of FCR in China. Peroxisomes are single-membrane organelles in eukaryotes that are involved in many important biochemical metabolic processes, including fatty acid β-oxidation. PEX11 is important proteins in peroxisome proliferation, while less is known in the fungus . The functions of FpPEX11a, FpPEX11b, and FpPEX11c in were studied using reverse genetics, and the results showed that FpPEX11a and FpPEX11b are involved in the regulation of vegetative growth and asexual reproduction. After deleting and , cell wall integrity was impaired, cellular metabolism processes including active oxygen metabolism and fatty acid β-oxidation were significantly blocked, and the production ability of deoxynivalenol (DON) decreased. In addition, the deletion of genes of and revealed a strongly decreased expression level of peroxisome-proliferation-associated genes and DON-synthesis-related genes. However, deletion of did not significantly affect these metabolic processes. Deletion of the three protein-coding genes resulted in reduced pathogenicity of . In summary, and play crucial roles in the growth and development, asexual reproduction, pathogenicity, active oxygen accumulation, and fatty acid utilization in .
Topics: Fusarium; Peroxisome Proliferators; Virulence; Plant Diseases; Reactive Oxygen Species; Soil; Fatty Acids
PubMed: 36293041
DOI: 10.3390/ijms232012184 -
International Journal of Molecular... Apr 2018The prevalence of obesity and atherosclerosis has substantially increased worldwide over the past several decades. Peroxisome proliferator-activated receptors (PPARs),... (Review)
Review
The prevalence of obesity and atherosclerosis has substantially increased worldwide over the past several decades. Peroxisome proliferator-activated receptors (PPARs), as fatty acids sensors, have been therapeutic targets in several human lipid metabolic diseases, such as obesity, atherosclerosis, diabetes, hyperlipidaemia, and non-alcoholic fatty liver disease. Constitutive androstane receptor (CAR) and liver X receptors (LXRs) were also reported as potential therapeutic targets for the treatment of obesity and atherosclerosis, respectively. Further clarification of the internal relationships between these three lipid metabolic nuclear receptors is necessary to enable drug discovery. In this review, we mainly summarized the cross-talk of PPARs-CAR in obesity and PPARs-LXRs in atherosclerosis.
Topics: Animals; Atherosclerosis; Constitutive Androstane Receptor; Humans; Liver X Receptors; Obesity; Peroxisome Proliferator-Activated Receptors; Receptors, Cytoplasmic and Nuclear
PubMed: 29690611
DOI: 10.3390/ijms19041260 -
PPAR Research 2018Peroxisome proliferator-activated receptor- (PPAR) is a class of ligand-activated nuclear transcription factors, which is a member of type II nuclear receptor... (Review)
Review
Peroxisome proliferator-activated receptor- (PPAR) is a class of ligand-activated nuclear transcription factors, which is a member of type II nuclear receptor superfamily. Previous studies demonstrate that PPAR is expressed in a variety of tumor tissues and is closely associated with the proliferation and prognosis of digestive system tumors by its roles in mediation of cell differentiation, induction of cell apoptosis, and inhibition of cell proliferation.
PubMed: 29483923
DOI: 10.1155/2018/5289859 -
PPAR Research 2017Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-dependent nuclear receptors, which control the transcription of genes involved in energy... (Review)
Review
Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-dependent nuclear receptors, which control the transcription of genes involved in energy homeostasis and inflammation and cell proliferation/differentiation. Alterations of PPARs' expression and/or activity are commonly associated with metabolic disorders occurring with obesity, type 2 diabetes, and fatty liver disease, as well as with inflammation and cancer. Emerging evidence now indicates that microRNAs (miRNAs), a family of small noncoding RNAs, which fine-tune gene expression, play a significant role in the pathophysiological mechanisms regulating the expression and activity of PPARs. Herein, the regulation of PPARs by miRNAs is reviewed in the context of metabolic disorders, inflammation, and cancer. The reciprocal control of miRNAs expression by PPARs, as well as the therapeutic potential of modulating PPAR expression/activity by pharmacological compounds targeting miRNA, is also discussed.
PubMed: 28167956
DOI: 10.1155/2017/7058424