2.PGC1α plays a pivotal role in renal fibrosis via regulation of fatty acid metabolism in renal tissue.
Rui ZHANG ; Jia ZENG ; Zhijun DENG ; Guangming YIN ; Long WANG ; Jing TAN
Journal of Central South University(Medical Sciences) 2022;47(6):786-793
Renal fibrosis is a common and irreversible pathological feature of end-stage renal disease caused by multiple etiologies. The role of inflammation in renal fibrosis tissue has been generally accepted. The latest view is that fatty acid metabolism disorder contributes to renal fibrosis. peroxisome proliferator activated receptor-gamma coactivator 1α (PGC1α) plays a key role in fatty acid metabolism, regulating fatty acid uptake and oxidized protein synthesis, preventing the accumulation of lipid in the cytoplasm, and maintaining a dynamic balanced state of intracellular lipid. In multiple animal models of renal fibrosis caused by acute or chronic kidney disease, or even age-related kidney disease, almost all of the kidney specimens show the down-regulation of PGC1α. Upregulation of PGC1α can reduce the degree of renal fibrosis in animal models, and PGC1α knockout animals exhibit severe renal fibrosis. Studies have demonstrated that AMP-activated protein kinase (AMPK), MAPK, Notch, tumor necrosis factor-like weak inducer of apoptosis (TWEAK), epidermal growth factor receptor (EGFR), non-coding RNA (ncRNAs), liver kinase B1 (LKB1), hairy and enhancer of split 1 (Hes1), and other pathways regulate the expression of PGC1α and affect fatty acid metabolism. But some of these pathways interact with each other, and the effect of the integrated pathway on renal fibrosis is not clear.
Animals
;
Fatty Acids
;
Fibrosis
;
Lipid Metabolism
;
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism*
;
Renal Insufficiency, Chronic
3.Generation of GABAergic interneuron-specific PGC-1α knockout mice.
Jia WANG ; Xianlu CHANG ; Jinjun QIAN ; Yang JIANG ; Chunyan WANG ; Yucong WANG ; Chi FENG ; Yongjie WANG ; Peihui XIA ; Ying ZHANG ; Danping WU ; Weining ZHANG
Chinese Journal of Medical Genetics 2017;34(2):200-204
OBJECTIVETo generate mice which are specific for peroxisomproliferator-activated receptor-γ coactivator-1(PGC-1α) knockout in the GABAergic interneuron.
METHODSConditional mice specific for PGC-1αwere introduced from the Jackson Laboratory, USA and initially inbred to obtain homozygote PGC-1αmice. The PGC-1αconditional mice were further crossed with Dlx5/6-Cre-IRES-EGFP transgenic mice to achieve specific knockout of PGC-1α in the GABAergic interneuron.
RESULTSThe offspring with specific knockout PGC-1α gene were successful for the generation of GABAergic interneuron, with the resulting genotype being PGC-1α.
CONCLUSIONThe PGC-1αmice were obtained through a proper crossing strategy, which has provided a suitable platform for studying the function of PGC-1α in neuropsychiatric diseases.
Animals ; Female ; Humans ; Interneurons ; metabolism ; Male ; Mice ; Mice, Knockout ; Neurodegenerative Diseases ; genetics ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; genetics ; gamma-Aminobutyric Acid ; metabolism
4.Increased hepatic peroxisome proliferator-activated receptor coactivator-1α expression precedes the development of insulin resistance in offspring of rats from severe hyperglycemic mothers.
Jing-mei MA ; Chan-juan ZENG ; Li ZHANG ; Chong SHOU ; Hui-xia YANG
Chinese Medical Journal 2012;125(7):1224-1229
BACKGROUNDPrenatal hyperglycaemia may increase metabolic syndrome susceptibility of the offspring. An underlying component of the development of these morbidities is hepatic gluconeogenic molecular dysfunction. We hypothesized that maternal hyperglycaemia will influence her offsprings hepatic peroxisome proliferator-activated receptor coactivator-1α (PGC-1α) expression, a key regulator of glucose production in hepatocytes.
METHODWe established maternal hyperglycaemia by streptozotocin injection to induce the maternal hyperglycaemic Wistar rat model. Offspring from the severe hyperglycemia group (SDO) and control group (CO) were monitored until 180 days after birth. Blood pressure, lipid metabolism indicators and insulin resistance (IR) were measured. Hepatic PGC-1α expression was analyzed by reverse transcription polymerase chain reaction and Western blotting. mRNA expression of two key enzymes in gluconeogenesis, glucose-6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK), were analyzed and compared.
RESULTSIn the SDO group, PGC-1α expression at protein and mRNA levels were increased, so were expression of G-6-Pase and PEPCK (P < 0.05). The above effects were seen prior to the onset of IR.
CONCLUSIONThe hepatic gluconeogenic molecular dysfunction may contribute to the metabolic morbidities experienced by this population.
Animals ; Female ; Hyperglycemia ; chemically induced ; physiopathology ; Insulin Resistance ; physiology ; Liver ; metabolism ; Male ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Peroxisome Proliferator-Activated Receptors ; metabolism ; Pregnancy ; Prenatal Exposure Delayed Effects ; RNA-Binding Proteins ; Rats ; Rats, Wistar ; Streptozocin ; toxicity ; Transcription Factors
5.Study of peroxisome proliferator-activated receptor-γ coactivator-1α expression and cytoapoptosis in masseter muscles of unilateral chewing rat.
Yingying YANG ; Tingting DING ; Qingting WU ; Jingjing KONG ; Dong QI ; Ping JI ;
Chinese Journal of Stomatology 2014;49(7):408-411
OBJECTIVETo investigate the changes of peroxisome proliferator- activated receptor-γ coactivator -1α (PGC-1α) mRNA and cytoapoptosis in the rats' masseter muscle which had been influenced by unilateral chewing, and to explore the theoretical foundation of changes in masticatory muscles induced by unilateral chewing.
METHODSThe animal models were established by extracting the Wistar rats' left maxillary molars. Thirty- six female Wistar rats were randomly divided into four groups of 2, 4, 6 and 8 weeks, nine each. In each group there were six rats with molar extracted and three as control. The Ca²⁺ level was detected by atomic spectrophotometric method. The relative expression of PGC-1α mRNA was detected by real- time fluorescent quantitative PCR. The apoptosis index was detected by Hoechst staining.
RESULTSThe Ca²⁺ level in the muscle on the extraction side were significantly higher than that in the controls in the beginning stage of unilateral chewing, and reached the peak at the 4th week [(43.62 ± 2.36) µg/g]. The relative expressions of PGC-1α increased from the beginning and reached the maximum level at the 4th week [extraction side: (1.57 ± 0.10); non-extraction side: (1.92 ± 0.06)], while the relative expressions of PGC-1α in 6 and 8 weeks decreased gradually [extraction side: (1.06 ± 0.08), (1.08 ± 0.07); non- extraction side: (1.09 ± 0.10), (1.11 ± 0.08)]. The changes of apoptosis index on non- extraction side increased continually and peaked at the 6th week [(38.56 ± 1.64)%].
CONCLUSIONSPGC-1α and cytoapoptosis played important roles in different stages of tissue remodeling induced by unilateral chewing.
Animals ; Apoptosis ; Female ; Masseter Muscle ; cytology ; metabolism ; Mastication ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; RNA, Messenger ; RNA-Binding Proteins ; Rats ; Rats, Wistar ; Transcription Factors ; metabolism
6.Role of neuropeptide Y and peroxisome proliferator-activated receptor γ coactivator-1α in stress cardiomyopathy.
Sunnassee ANANDA ; Yunyun WANG ; Shaohua ZHU ; Rongshuai WANG ; Xiaowei ZHOU ; Luo ZHUO ; Tingyi SUN ; Liang REN ; Qian LIU ; Hongmei DONG ; Yan LIU ; Liang LIU
Journal of Huazhong University of Science and Technology (Medical Sciences) 2012;32(6):823-828
Death following situations of intense emotional stress has been linked to the cardiac pathology described as stress cardiomyopathy, whose pathomechanism is still not clear. In this study, we sought to determine, via an animal model, whether the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α) and the amino peptide neuropeptide Y (NPY) play a role in the pathogenesis of this cardiac entity. Male Sprague-Dawley rats in the experimental group were subjected to immobilization in a plexy glass box for 1 h, which was followed by low voltage electric foot shock for about 1 h at 10 s intervals in a cage fitted with metallic rods. After 25 days the rats were sacrificed and sections of their hearts were processed. Hematoxylin-eosin staining of cardiac tissues revealed the characteristic cardiac lesions of stress cardiomyopathy such as contraction band necrosis, inflammatory cell infiltration and fibrosis. The semi-quantitative RT-PCR analysis for PGC-1α mRNA expression showed significant overexpression of PGC1-α in the stress-subjected rats (P<0.05). Fluorescence immunohistochemistry revealed a higher production of NPY in the stress-subjected rats as compared to the control rats (P=0.0027). Thus, we are led to conclude that following periods of intense stress, an increased expression of PGC1-α in the heart and an overflow of NPY may lead to stress cardiomyopathy and even death in susceptible victims. Moreover, these markers can be used to identify stress cardiomyopathy as the cause of sudden death in specific cases.
Animals
;
Cardiomyopathies
;
metabolism
;
Myocytes, Cardiac
;
metabolism
;
Neuropeptide Y
;
metabolism
;
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
;
Rats
;
Rats, Sprague-Dawley
;
Stress, Physiological
;
physiology
;
Transcription Factors
;
metabolism
7.Research progresses on PGC-1α, a key energy metabolic regulator.
Hui-Ting WANG ; Yan-Chen ZHANG ; Meng-Yi XU ; Wen-Xiang ZHANG ; Chang LIU ; Si-Yu CHEN
Acta Physiologica Sinica 2020;72(6):804-816
Disturbance of the energy balance, when the energy intake exceeds its expenditure, is a major risk factor for the development of metabolic syndrome (MS). The peroxisome proliferator activated receptor γ (PPARγ) coactivator-1α (PGC-1α) functions as a key regulator of energy metabolism and has become a hotspot in current researches. PGC-1α sensitively responds to the environmental stimuli and nutrient signals, and further selectively binds to different transcription factors to regulate various physiological processes, including glucose metabolism, lipid metabolism, and circadian clock. In this review, we described the gene and protein structure of PGC-1α, and reviewed its tissue-specific function in the regulation of energy homeostasis in various mammalian metabolic organs, including liver, skeletal muscle and heart, etc. At the meanwhile, we summarized the application of potential small molecule compounds targeting PGC-1α in the treatment of metabolic diseases. This review will provide theoretical basis and potential drug targets for the treatment of metabolic diseases.
Animals
;
Energy Metabolism
;
Homeostasis
;
Lipid Metabolism
;
Liver/metabolism*
;
Muscle, Skeletal/metabolism*
;
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism*
;
Transcription Factors/metabolism*
8.Effects of PGC1
Jungang NIE ; Na TA ; Lijuan LIU ; Guoxiang SHI ; Ting KANG ; Zeqi ZHENG
Journal of Central South University(Medical Sciences) 2020;45(10):1155-1163
OBJECTIVES:
Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) controls mitochondrial biogenesis, but its role in cardiovascular diseases is unclear. The purpose of this study is to explore the effect of PGC1α on myocardial ischemia-reperfusion injury and the underlying mechanisms.
METHODS:
The transverse coronary artery of SD rat was ligated for 30 minutes followed by 2 hours of reperfusion. Triphenyltetrazolium chloride (TTC) staining was performed to measure the area of myocardial infarction. Immunohistochemistry and Western blotting were used to detect the PGC1α expression in myocardium. The rat cardiomyocyte H9C2 was subjected to hypoxia/reoxygenation (H/R) with the knockdown of PGC1α or hypoxia- inducible factor 1α (HIF-1α), or with treatment of metformin. Western blotting was used to detect the expression of PGC1α, HIF-1α, p21, BAX, and caspase-3. CCK-8 was performed to detect cell viability, and flow cytometry was used to detect apoptosis and mitochondrial superoxide (mitoSOX) release. RT-qPCR was used to detect the mRNA expression of PGC1α and HIF-1α. Besides, chromatin immunoprecipitation (ChIP)-qPCR and luciferase reporter gene assay were applied to detect the transcriptional regulation effect of HIF-1α on PGC1α.
RESULTS:
After I/R, the PGC1α expression was increased in infarcted myocardium. H/R induced H9C2 cell apoptosis (
CONCLUSIONS
After I/R, HIF-1α up-regulates the expression of PGC1α, leading to an increase in ROS production and aggravation of injury. Metformin can inhibit the accumulation of HIF-1α during hypoxia and effectively protect myocardium from ischemia/reperfusion injury.
Animals
;
Apoptosis
;
Hypoxia-Inducible Factor 1, alpha Subunit/genetics*
;
Myocardial Reperfusion Injury/genetics*
;
Myocytes, Cardiac/metabolism*
;
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism*
;
Rats
;
Rats, Sprague-Dawley
;
Reperfusion Injury
9.Effects of Mitochondrial Dysfunction via AMPK/PGC-1 α Signal Pathway on Pathogenic Mechanism of Diabetic Peripheral Neuropathy and the Protective Effects of Chinese Medicine.
Chinese journal of integrative medicine 2019;25(5):386-394
Diabetic peripheral neuropathy (DPN) is a progressive neurodegenerative disease of peripheral nervous system with high energy requirement. The adenosine monophosphate-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor- γ coactivator 1 α (PGC-1 α) axis plays a key role in regulating mitochondrial energy metabolism. Increasing preclinical evidences have shown that inhibition of AMPK/PGC-1 α pathway leading to mitochondrial dysfunction in neurons or Schwann cells contributes to neuron apoptosis, distal axonopathy and nerve demyelination in DPN. Some Chinese medicine formulae or extracts from herbs may have potential neuroprotective effects on DPN via activating AMPK/PGC-1 α pathway and improving mitochondrial function.
AMP-Activated Protein Kinases
;
metabolism
;
Diabetic Neuropathies
;
drug therapy
;
pathology
;
Humans
;
Medicine, Chinese Traditional
;
Mitochondria
;
metabolism
;
pathology
;
Neuroprotective Agents
;
therapeutic use
;
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
;
metabolism
;
Signal Transduction
10.Mechanism of Zexie Decoction in improvement of nonalcoholic fatty liver disease based on LKB1/AMPK/PGC-1α pathway.
Meng-Yao WANG ; Gai GAO ; Er-Wen LI ; Xiao-Wei ZHANG ; Hui WANG ; Jiang-Yan XU ; Zhen-Qiang ZHANG ; Pan WANG ; Zhi-Shen XIE
China Journal of Chinese Materia Medica 2022;47(2):453-460
The present study investigated the pharmaceutical effect and underlying mechanism of Zexie Decoction(ZXD) on nonalcoholic fatty liver disease(NAFLD) in vitro and in vivo via the LKB1/AMPK/PGC-1α pathway based on palmitic acid(PA)-induced lipid accumulation model and high-fat diet(HFD)-induced NAFLD model in mice. As revealed by the MTT assay, ZXD had no effect on HepG2 activity, but dose-dependently down-regulated alanine aminotransferase(ALT) and aspartate aminotransferase(AST) in the liver cell medium induced by PA, and decreased the plasma levels of ALT and AST, and total cholesterol(TC) and triglyceride(TG) levels in the liver. Nile red staining showed PA-induced intracellular lipid accumulation, significantly increased lipid accumulation of hepatocytes induced by PA, suggesting that the lipid accumulation model in vitro was properly induced. ZXD could effectively improve the lipid accumulation of hepatocytes induced by PA. Oil red O staining also demonstrated that ZXD improved the lipid accumulation in the liver of HFD mice. JC-1 staining for mitochondrial membrane potential indicated that ZXD effectively reversed the decrease in mitochondrial membrane potential caused by hepatocyte injury induced by PA, activated PGC-1α, and up-regulated the expression of its target genes, such as ACADS, CPT-1α, CPT-1β, UCP-1, ACSL-1, and NRF-1. In addition, as revealed by the Western blot and immunohistochemistry, ZXD up-regulated the protein expression levels of LKB1, p-AMPK, p-ACC, and PGC-1α in vivo and in vitro. In conclusion, ZXD can improve NAFLD and its mechanism may be related to the regulation of the LKB1/AMPK/PGC-1α pathway.
AMP-Activated Protein Kinases/metabolism*
;
Alanine Transaminase/metabolism*
;
Animals
;
Diet, High-Fat
;
Liver/metabolism*
;
Mice
;
Mice, Inbred C57BL
;
Non-alcoholic Fatty Liver Disease/genetics*
;
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha