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Abstract The imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophages plays a critical role in the pathogenesis of sepsis-induced acute lung injury (ALI). Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may modulate macrophage polarization toward the M2 phenotype by altering mitochondrial activity. This study aimed to investigate the role of the PGC-1α agonist pioglitazone (PGZ) in modulating sepsis-induced ALI. A mouse model of sepsis-induced ALI was established using cecal ligation and puncture (CLP). An in vitro model was created by stimulating MH-S cells with lipopolysaccharide (LPS). qRT-PCR was used to measure mRNA levels of M1 markers iNOS and MHC-II and M2 markers Arg1 and CD206 to evaluate macrophage polarization. Western blotting detected expression of peroxisome proliferator-activated receptor gamma (PPARγ) PGC-1α, and mitochondrial biogenesis proteins NRF1, NRF2, and mtTFA. To assess mitochondrial content and function, reactive oxygen species levels were detected by dihydroethidium staining, and mitochondrial DNA copy number was measured by qRT-PCR. In the CLP-induced ALI mouse model, lung tissues exhibited reduced PGC-1α expression. PGZ treatment rescued PGC-1α expression and alleviated lung injury, as evidenced by decreased lung wet-to-dry weight ratio, pro-inflammatory cytokine secretion (tumor necrosis factor-α, interleukin-1β, interleukin-6), and enhanced M2 macrophage polarization. Mechanistic investigations revealed that PGZ activated the PPARγ/PGC-1α/mitochondrial protection pathway to prevent sepsis-induced ALI by inhibiting M1 macrophage polarization. These results may provide new insights and evidence for developing PGZ as a potential ALI therapy.
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Background Long-term exposure to arsenic can cause liver injury of varying degrees. Mitochondrial damage may be an early key event of arsenic-induced liver injury. Silent mating type information regulation 2 homolog 1 (SIRT1)/ recombinant peroxisome proliferators-activated receptor gamma coactivator 1 alpha (PGC-1α) is an important pathway regulating mitochondrial mass and function. However, whether arsenic-induced liver injury is related to mitochondrial dysfunction mediated by SIRT1/PGC-1α pathway remains unclear. Objective To investigate potential effects of sodium arsenite (NaAsO2) on mitochondrial function and expressions of SIRT1/PGC-1α pathway-related proteins in human normal liver cell. Methods Human normal liver cells (MIHA cells) were used as the research object. MIHA cells were treated with different concentrations of NaAsO2 (0, 5, 10 and 20 μmol·L−1) for 24 h, and the cells were collected for study. The ultrastructure of mitochondria was observed by transmission electron microscopy, adenosine triphosphate (ATP) concentration by fluorescence method, mitochondrial membrane potential (MMP) level by flow cytometry, and SIRT1, PGC-1α and their downstream nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM) protein expression levels by Western blotting. One-way analysis of variance and trend test were used for data statistical analysis. Results The viability of MIHA cells decreased gradually with the increase of NaAsO2 concentration (F=6495.47, P<0.001). The transmission electron microscope observation showed that the size of mitochondria in the 10 μmol·L−1 NaAsO2 treatment group was different, and the mitochondria were swollen or elongated in a rod-like shape. The mitochondria in the 20 μmol·L−1 NaAsO2 treatment group swelled like air spheres or vacuoles. The ATP concentration and MMP level of MIHA cells gradually decreased with the increase of NaAsO2 concentration (Ftrend of ATP=172.28, Ftrend of MMP=59.91, both Ps<0.001). Compared with the control group, the protein expression levels of SIRT1, PGC-1α, NRF1, and TFAM were not significantly changed in the 5 μmol·L−1 NaAsO2 treatment group, while the protein expression levels of SIRT1, PGC-1α, and TFAM were decreased in the 10 μmol·L−1 NaAsO2 treatment group, and the protein expression levels of SIRT1, PGC-1α, and NRF1 were decreased in the 20 μmol·L−1 NaAsO2 treatment group. The results of trend test showed that the protein expression levels of SIRT1, PGC-1α, NRF1, and TFAM decreased gradually with the increase of NaAsO2 concentration (Ftrend of SIRT1=47.07, P<0.001; Ftrend of PGC-1α=15.17, P<0.01; Ftrend of NRF1=13.54, P<0.01; F trend of TFAM=4.20, P<0.05). Conclusion The down-regulation of SIRT1/PGC-1α and its downstream NRF1 and TFAM may be involved in NaAsO2-induced mitochondrial dysfunction in liver cells.
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Peroxisome proliferator-activated receptor γ coactivator 1-alpha (PGC-1α) is a member of superfamily of transcriptional co-regulators. It was first discovered to be related to the adaptive thermogenesis of brown adipose tissue. Later, it has been discovered that PGC-la can also regulate glucose and lipid metabolism and vascular endothelial function, thus influence the occurrence and development of obesity-related metabolic diseases such as hyperlipidemia, type II diabetes and hypertension. Drugs targeting PGC-1α are promising for the prevention and treatment of these diseases. Here we review the research progress on regulation of PGC-1α in obesity related metabolic diseases, aiming to provide theoretical basis for the development of drugs targeting PGC-1α.
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Objective:To observe the effects of Da Chaihutang on Cyclic adenosine monophosphate （cAMP）-response element binding protein （CREB）/peroxisome proliferator-activated receptor-gamma coactivator-1 alpha （PGC-1<italic>α</italic>） pathway in nutritionally obese rats and the protective mechanism on liver mitochondria. Method:A total of 120 8-week-old male SD rats were randomly divided into a control group （<italic>n</italic>=20） and an experimental group （<italic>n</italic>=100）. The rats in the control group were fed on a normal diet， while those in the experimental group were administered with a high-fat feed. Successfully modeled rats were randomly divided into a model group， a positive drug （metformin） group， and low-， medium- and high-dose Da Chaihutang groups （4.25， 8.5， and 17 g∙kg<sup>-1</sup>， respectively）， with 20 rats in each group. After treatment with Da Chaihutang， the body weight， Lee's index， liver mitochondrial membrane potential and mitochondrial ultrastructure， PGC-1<italic>α </italic>expression and CREB phosphorylation of each group were measured and compared. Result:Compared with the control group， the model group showed increased body weight and Lee's index （<italic>P</italic><0.01）， whereas decreased mitochondrial membrane potential， PGC-1<italic>α</italic> expression， and CREB phosphorylation level （<italic>P</italic><0.01）. As compared with the model group， Da Chaihutang significantly reduced the body weight and Lee's index of obese rats （<italic>P</italic><0.05， <italic>P</italic><0.01）， enhanced liver mitochondrial membrane potential （<italic>P</italic><0.05， <italic>P</italic><0.01） to protect the integrity of mitochondrial structure， up-regulated PGC-1<italic>α</italic> expression and promoted CREB phosphorylation （<italic>P</italic><0.05， <italic>P</italic><0.01）. Conclusion:Da Chaihutang protects the structure and function of mitochondria and inhibits weight gain in obese rats by activating the CREB/PGC-1<italic>α</italic> pathway.
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ObjectiveTo investigate the association of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) rs8192678 single nucleotide polymorphism (SNP) with the risk of nonalcoholic fatty liver disease (NAFLD) and the influence of PPARGC1A rs8192678 SNP on NAFLD-related biochemical parameters. MethodsA total of 119 NAFLD patients who attended Qingdao Municipal Hospital Affiliated to Qingdao University from December 2017 to December 2018 were enrolled as NAFLD group, and 213 individuals who underwent physical examination during the same period of time were enrolled as control group. Clinical data and blood samples were collected from all subjects to measure related biochemical parameters and detect PPARGC1A rs8192678 SNP. The chi-square test was used to determine whether the genotype distribution of samples was in accordance with the Hardy-Weinberg equilibrium. The t-test or the Wilcoxon rank-sum test was used for comparison of continuous data between two groups, and the chi-square test was used for comparison of categorical data between two groups. A binary logistic regression analysis was used to investigate the risk factors for NAFLD. ResultsThere were no significant differences in the genotype and allele frequencies of PPARGC1A rs8192678 between the NAFLD group and the control group (χ2=0.011 and 0.015, P=0.918 and 0.904). The binary logistic regression analysis showed that CT genotype of PPARGC1A rs8192678 was not a risk factor for NAFLD (odds ratio=0.951, 95% confidence interval: 0.368-2.457, P=0.918). In the NAFLD group, the patients carrying CT genotype had a significantly higher level of gamma-glutamyl transpeptidase (GGT) than those carrying CC genotype (Z=-2.331, P=0.020). ConclusionPPARGC1A rs8192678 SNP does not increase the risk of NAFLD, while NAFLD patients carrying CT genotype tend to have a higher serum level of GGT.
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Cardiovascular disease is currently the number one killer of human health. Studies have shown that peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a key factor in physiological processes such as energy metabolism and oxidative stress, which also involved in regulating mitochondrial biosynthesis. PGC-1α is closely related to the occurrence and development of atherosclerosis, coronary heart disease, atrial fibrillation, cardiomyopathy, myocardial hypertrophy, heart failure and other cardiovascular diseases. This article briefly describes the research progress of PGC-1α in cardiovascular diseases.
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<p><b>Background</b>Shensong Yangxin Capsule (SSYX), traditional Chinese medicine, has been used to treat arrhythmias, angina, cardiac remodeling, cardiac fibrosis, and so on, but its effect on cardiac energy metabolism is still not clear. The objective of this study was to investigate the effects of SSYX on myocardium energy metabolism in angiotensin (Ang) II-induced cardiac hypertrophy.</p><p><b>Methods</b>We used 2 μl (10 mol/L) AngII to treat neonatal rat cardiomyocytes (NRCMs) for 48 h. Myocardial α-actinin staining showed that the myocardial cell volume increased. Expression of the cardiac hypertrophic marker-brain natriuretic peptide (BNP) messenger RNA (mRNA) also increased by real-time polymerase chain reaction (PCR). Therefore, it can be assumed that the model of hypertrophic cardiomyocytes was successfully constructed. Then, NRCMs were treated with 1 μl of different concentrations of SSYX (0.25, 0.5, and 1.0 μg/ml) for another 24 h. To explore the time-depend effect of SSYX on energy metabolism, 0.5 μg/ml SSYX was added into cells for 0, 6, 12, 24, and 48 h. Mitochondria was assessed by MitoTracker staining and confocal microscopy. mRNA and protein expression of mitochondrial biogenesis-related genes - Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), energy balance key factor - adenosine monophosphate-activated protein kinase (AMPK), fatty acids oxidation factor - carnitine palmitoyltransferase-1 (CPT-1), and glucose oxidation factor - glucose transporter- 4 (GLUT-4) were measured by PCR and Western blotting analysis.</p><p><b>Results</b>With the increase in the concentration of SSYX (from 0.25 to 1.0 μg/ml), an increased mitochondrial density in AngII-induced cardiomyocytes was found compared to that of those treated with AngII only (0.25 μg/ml, 18.3300 ± 0.8895 vs. 24.4900 ± 0.9041, t = 10.240, P < 0.0001; 0.5 μg/ml, 18.3300 ± 0.8895 vs. 25.9800 ± 0.8187, t = 12.710, P < 0.0001; and 1.0 μg/ml, 18.3300 ± 0.8895 vs. 24.2900 ± 1.3120, t = 9.902, P < 0.0001; n = 5 per dosage group). SSYX also increased the mRNA and protein expression of PGC-1α (0.25 μg/ml, 0.8892 ± 0.0848 vs. 1.0970 ± 0.0994, t = 4.319, P = 0.0013; 0.5 μg/ml, 0.8892 ± 0.0848 vs. 1.2330 ± 0.0564, t = 7.150, P < 0.0001; and 1.0 μg/ml, 0.8892 ± 0.0848 vs. 1.1640 ± 0.0755, t = 5.720, P < 0.0001; n = 5 per dosage group), AMPK (0.25 μg/ml, 0.8872 ± 0.0779 vs. 1.1500 ± 0.0507, t = 7.239, P < 0.0001; 0.5 μg/ml, 0.8872 ± 0.0779 vs. 1.2280 ± 0.0623, t = 9.379, P < 0.0001; and 1.0 μg/ml, 0.8872 ± 0.0779 vs. 1.3020 ± 0.0450, t = 11.400, P < 0.0001; n = 5 per dosage group), CPT-1 (1.0 μg/ml, 0.7348 ± 0.0594 vs. 0.9880 ± 0.0851, t = 4.994, P = 0.0007, n = 5), and GLUT-4 (0.5 μg/ml, 1.5640 ± 0.0599 vs. 1.7720 ± 0.0660, t = 3.783, P = 0.0117; 1.0 μg/ml, 1.5640 ± 0.0599 vs. 2.0490 ± 0.1280, t = 8.808, P < 0.0001; n = 5 per dosage group). The effect became more obvious with the increasing concentration of SSYX. When 0.5 μg/ml SSYX was added into cells for 0, 6, 12, 24, and 48 h, the expression of AMPK (6 h, 14.6100 ± 0.6205 vs. 16.5200 ± 0.7450, t = 3.456, P = 0.0250; 12 h, 14.6100 ± 0.6205 vs. 18.3200 ± 0.9965, t = 6.720, P < 0.0001; 24 h, 14.6100 ± 0.6205 vs. 21.8800 ± 0.8208, t = 13.160, P < 0.0001; and 48 h, 14.6100 ± 0.6205 vs. 23.7400 ± 1.0970, t = 16.530, P < 0.0001; n = 5 per dosage group), PGC-1α (12 h, 11.4700 ± 0.7252 vs. 16.9000 ± 1.0150, t = 7.910, P < 0.0001; 24 h, 11.4700 ± 0.7252 vs. 20.8800 ± 1.2340, t = 13.710, P < 0.0001; and 48 h, 11.4700 ± 0.7252 vs. 22.0300 ± 1.4180, t = 15.390; n = 5 per dosage group), CPT-1 (24 h, 15.1600 ± 1.0960 vs. 18.5800 ± 0.9049, t = 6.048, P < 0.0001, n = 5), and GLUT-4 (6 h, 10.2100 ± 0.9485 vs. 12.9700 ± 0.8221, t = 4.763, P = 0.0012; 12 h, 10.2100 ± 0.9485 vs. 16.9100 ± 0.8481, t = 11.590, P < 0.0001; 24 h, 10.2100 ± 0.9485 vs. 19.0900 ± 0.9797, t = 15.360, P < 0.0001; and 48 h, 10.2100 ± 0.9485 vs. 14.1900 ± 0.9611, t = 6.877, P < 0.0001; n = 5 per dosage group) mRNA and protein increased gradually with the prolongation of drug action time.</p><p><b>Conclusions</b>SSYX could increase myocardial energy metabolism in AngII-induced cardiac hypertrophy. Therefore, SSYX might be considered to be an alternative therapeutic remedy for myocardial hypertrophy.</p>
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Animals , Rats , Angiotensin II , Metabolism , Cardiomegaly , Drug Therapy , Energy Metabolism , Medicine, Chinese Traditional , Myocardium , Myocytes, CardiacABSTRACT
AIM:To investigate effects of resveratrol on mitochondrial DNA copy in retinal vascular endothelial cells cultured under high glucose conditions and its mechanism.METHODS:Human retinal vascular endothelial cells were cultured in low glucose or high glucose medium,the genomic DNA was extracted and copy number of mitochondrial DNA was detected by real-time PCR.Effects of resveratrol on the mitochondrial DNA copy in retinal vascular endothelial cells cultured under high glucose medium were studied.The expression of mitochondrial transcription factor A (TFAM) and acetylated proliferator-activated receptor coactivator-1 alpha (PGC-1α) were analyzed by Western blot and coimmunoprecipitation.RESULTS:High glucose inhibited the copy number of mitochondrial DNA in retinal vascular endothelial cells.However,resveratrol decreased the level of acetylated PGC-1α in retinal vascular endothelial cells,increased the expression of TFAM and the copy number of mitochondrial DNA.CONCLUSION:Resveratrol may improve mitochondrial function of retinal vascular endothelial cells exposed to a high glucose environment via activation of the PCG-1α-TFAM signaling pathway.
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In mitochondria,peroxisome proliferator activated receptor (PPARs) and PPARγ coactivator-1 alpha (PGC-1α) work together to regulate the energy metabolism.Mitochondrial cardiomyopathy is a disease characterized by myocardial damage and abnormal energy metabolic that results from abnormalities in mitochondria quantity,structure and function in cardiac myocytes.However,there is inadequate knowledge on the pathogenesis of mitochondrial cardiomyopathy.In this paper,we summarize the roles played by PPARs and PGC-1α in mitochondrial cardiomyopathy.We expect this paper will provide some new clues for further studies of mitochondrial cardiomyopathy.
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Background and purpose: Lysine specific demethylase 1(LSD1) is an important chromatin modifier. It epigenetically regulates gene expression pattern through chromatin modification and participates in maintenance of tumor malignant properties, such as oncogenesis, development, invasion, migration and metabolic transformation. SIRT3 (sirtuin 3) is a mitochondria localized tumor suppressor and regulates tumor metabolic transformation and oxidative stress. The correlation between LSD1 and SIRT3 has never been reported before. This study aimed to elucidate the correlation between LSD1 and SIRT3 with gene transcriptional regulation methods. Methods: RNA interference technique, co-immunoprecipitation assay(CoIP), chromatin immune-precipitation assay(ChIP) and ifrelfy luciferase activity assay were employed to elucidate the correlation between LSD1 and SIRT3 in pancreatic cancer. Results:mRNA and protein levels of SIRT3 were signiifcantly elevated in LSD1 knock-down PANC-1 cells. LSD1 interacts with PGC-1α, an important regulator of SIRT3 gene expression. LSD1 and PGC-1αoccupied the same region in SIRT3 promoter region through ChIP analysis. Luciferase activity assay validated LSD1 as a negative regulator of PGC-1αin SIRT3 gene transcriptional regulation. Conclusion:LSD1, as an important tumor promoter, negatively regulates the expression of tumor suppressor gene SIRT3, these results provide important clues for the role that LSD1 plays in aberrant metabolism and oxidative stress.
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BACKGROUND: We investigated the effects of the common polymorphisms in the peroxisome proliferator- activated receptor gamma2 (PPAR-gamma2 Pro12Ala) and in PPAR-gamma coactivator 1alpha (PGC-1alpha Gly482Ser) genes on the association with the nephropathy of Korean patients with type 2 diabetes mellitus. METHODS: A total of 113 patients with type 2 diabetes and 123 patients with diabetic nephropathy were enrolled in this study. The Pro12Ala polymorphism of the PPAR-gamma2 gene and the Gly482Ser polymorphism in the PGC-1alpha gene were determined with the polymerase chain reaction amplification, BstU-I and Msp I enzyme digestion, and gel electrophoresis. RESULTS: The genotype and allelic frequency of PPAR-gamma2 Pro12Ala gene were not different statistically between the diabetic nephropathy and the control. The genotype of PGC-1alpha Gly482Ser in diabetic nephropathy was also not different from those in control. The allelic frequency and carriage rate of Ser allele in PGC-1alpha Gly482Ser were significantly higher in patients with diabetic nephropathy than those in control (respectively, p<0.05). CONCLUSION: The polymorphisms of the PGC-1alpha Gly482Ser gene are significantly associated with the nephropathy in Korean patients with type 2 diabetes mellitus.
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BACKGROUND: We investigated the effects of the common polymorphisms in the peroxisome proliferator- activated receptor gamma2 (PPAR-gamma2 Pro12Ala) and in PPAR-gamma coactivator 1alpha (PGC-1alpha Gly482Ser) genes on the association with the nephropathy of Korean patients with type 2 diabetes mellitus. METHODS: A total of 113 patients with type 2 diabetes and 123 patients with diabetic nephropathy were enrolled in this study. The Pro12Ala polymorphism of the PPAR-gamma2 gene and the Gly482Ser polymorphism in the PGC-1alpha gene were determined with the polymerase chain reaction amplification, BstU-I and Msp I enzyme digestion, and gel electrophoresis. RESULTS: The genotype and allelic frequency of PPAR-gamma2 Pro12Ala gene were not different statistically between the diabetic nephropathy and the control. The genotype of PGC-1alpha Gly482Ser in diabetic nephropathy was also not different from those in control. The allelic frequency and carriage rate of Ser allele in PGC-1alpha Gly482Ser were significantly higher in patients with diabetic nephropathy than those in control (respectively, p<0.05). CONCLUSION: The polymorphisms of the PGC-1alpha Gly482Ser gene are significantly associated with the nephropathy in Korean patients with type 2 diabetes mellitus.