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FLASH GENE
Symbol PPARGC1A contributors: mct/shn - updated : 21-06-2017
HGNC name peroxisome proliferator-activated receptor gamma, coactivator 1 alpha
HGNC id 9237
Location 4p15.2      Physical location : 23.793.644 - 23.891.700
Synonym name
  • peroxisome proliferative activated receptor, gamma, coactivator 1
  • peroxisome proliferative activated receptor, gamma, coactivator 1, alpha
  • peroxisome proliferator-activated receptor gamma coactivator 1-alpha
  • PPAR gamma coactivator variant form
  • ligand effect modulator-6
  • Synonym symbol(s) PGC1, LEM6, PGC1A, PPARGC1, PGC-1v, L-PGC-1alpha, PGC-1-alpha, PPARGC-1-alpha
    DNA
    TYPE functioning gene
    STRUCTURE 98.06 kb     13 Exon(s)
    MAPPING cloned Y linked N status provisional
    Map pter - D4S2933 - D4S425 - PPARGC1A - D4S3013 - D4S404 - cen
    Authors Esterbauer (99)
    RNA
    TRANSCRIPTS type messenger
    text
  • a novel promoter that is located in a large CpG island 583 kb upstream of exon 1 (PMID: 22589246)
  • CREB and the MyoD family of transcription factors activate an alternative promoter (PMID: 19233136)
  • identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    13 - 6318 91 798 present in skeletal muscle, localized to the nucleus 2012 22589246
    - - - - - mRNA in skeletal muscle not only of mice but also of humans 2012 22589246
  • also called PPARGC1Ab
  • muscle-enriched isoform
  • muscle-specific transcription factors MYOD1 and MYF6 transactivated the promoter through interaction with a proximal E-box motif
  • strongly induced by exercise in skeletal muscle
  • - - - - 268 - 2012 22589246
  • also called NT-PGC-1A
  • contains the transactivation and nuclear receptor interaction domains but is missing key domains involved in nuclear localization, interaction with other transcription factors, and protein degradation
  • N-truncated PGC-1A retaining the N-terminal transcriptional activation and NR-interacting domains but is missing all domains within aa 268797 of the full-length protein
  • EXPRESSION
    Type
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly Homo sapiens
    Digestiveliver     Homo sapiens
    Nervousbrain     Homo sapiens
    Urinarykidney     Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumcardiac highly Homo sapiens
    Muscularstriatumskeletal highly Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Muscularmyocyte
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • three protein kinase phosphorylation sites
  • a LXXLL motif
  • two SR domains
  • a RNA recognition motif (RRM)
  • a bipartite nuclear localization signal (NLS)
  • HOMOLOGY
    interspecies ortholog to Ppargc1a, Mus musculus
    ortholog to Ppargc1a, Rattus norvegicus
    ortholog to PPARGC1A, Pan troglodytes
    ortholog to ppargc1a, Danio rerio
    Homologene
    FAMILY
    CATEGORY regulatory , DNA associated
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus
    basic FUNCTION
  • promoting insulin resistance in liver through PPARA-dependent induction of TRIB3
  • playing an important role in energy metabolism by co-ordinating transcription programmes of mitochondrial biogenesis, adaptive thermogenesis and fatty-acid beta-oxydation
  • stimulates mitochondrial biogenesis and respiration in muscle cells through an induction of uncoupling protein 2 and through regulation of the nuclear respiratory factors
  • plays a key role in the transcriptional control of genes encoding mitochondrial fatty acid beta-oxidation enzymes
  • a coactivator of PPARalpha in the transcriptional control of mitochondrial FAO capacity
  • a key modulator of hepatic gluconeogenesis and as a central target of the insulin-cAMP axis in liver
  • a bona fide coactivator for RXRalpha
  • also coactivating transcription factor for gluco-neogenesis in liver and glucose uptake in muscle
  • may be also involved in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity
  • can regulate the activities of cAMP response element binding protein (CREB) and nuclear respiratory factors (NRFs)
  • activating and determining specificity of PPAR subtypes
  • activating transcription trhough glucocorticoid receptors
  • activating liver recpetors N1RH2, N1RH3
  • regulating SOX9-dependent chondrogenesis in mesenchymal stem cells and chondrocytes
  • have a key role in the control of energy metabolism in the early stages of Huntington's disease pathogenesis
  • stimulates the expression of clock genes, notably Bmal1 and Rev-erbalpha , through coactivation of the ROR family of orphan nuclear receptors
  • a key component of the circadian oscillator that integrates the mammalian clock and energy metabolism
  • necessary for the postnatal metabolic and functional maturation of heart and brown adipose tissue
  • controls mitochondrial biogenesis and energy homeostasis
  • PPARGC1A and PPARGC1B control mitochondrial capacity in an additive and independent manner
  • its central function in many cellular contexts and in particular in brown adipocytes is to promote mitochondrial biogenesis
  • multi-functional coactivator that is involved in the regulation of cardiac mitochondrial functional capacity and cellular energy metabolism
  • can ameliorate cardiac Ca2+ cycling and improve cardiac work output in response to physiological stress
  • plays a key role in decreasing cellular Ca2+-overload, reorganizing cardiac function and improving cardiac adaptability
  • capacity of PPARGC1A and PPARGC1B to inhibit FOXO3 and NFkappaB actions and proteolysis, which helps explain how exercise prevents muscle atrophy
  • critical to peroxisomal physiology, establishing a role for this factor as a fundamental orchestrator of cellular adaptation to energy demands
  • EPAS1 acts downstream of PPARGC1A as a key regulator of a muscle fiber-type program and the adaptive response to exercise
  • regulates enterocyte cell fate and protects against tumorigenesis
  • ability to promote anchorage-independent growth required interaction with ESRRA, and treatment with an inhibitor of ESRRA impeded anchorage-independent growth
  • PPARGC1A, and PPARGC1B modulate mitochondrial biogenesis and energy homeostasis
  • coordinately regulates mitochondrial and fatty acid metabolism to promote tumor growth
  • role in regulating TP53-mediated cell fate decisions in response to metabolic stress
  • stimulates the expression of several muscle gene products that are potentially secreted, including FNDC5
  • required for the induction of the mitochondrial transcriptional program and the increase in mitochondrial density observed during calorie restriction
  • skeletal muscle PPRGC1A is required for the mitochondrial, but not the metabolic, response to calorie restriction
  • implicated in the pathogenesis of neurodegenerative disorders (Huntington disease)
  • promoted HTT turnover and the elimination of protein aggregates by activating TFEB, a master regulator of the autophagy-lysosome pathway
  • SUMOylation of PPARGC1A controlled by SENP1 plays an important role in mitochondrial biogenesis and function
  • CELLULAR PROCESS nucleotide, transcription, initiation
    nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS development , digestion
    text
  • homeostasis of energy adaptive thermogenesis
  • driving the formation of slow-twitch muscle fibers
  • mitochondrial biogenesis and respiration in muscle and gluconeogenesis in liver
  • PATHWAY
    metabolism carbohydrate , energetic
    signaling
    triggering hepatic gluconeogenic enzymes including, PEPCK, G6PC
    a component ESRRA, PPARGC1A, and BCL3 form a complex on an ESRRA-responsive element within the pyruvate dehydrogenase kinase 4 gene promoter in cardiac myocytes
    INTERACTION
    DNA binding
    RNA binding
    small molecule nucleotide,
    protein
  • histone acetyltransferases steroid receptor coactivator-1 (SRC-1) and CREB binding protein (CBP)/p300
  • PPARalpha
  • hinge domain of PPARgamma and estrogen receptor-alpha
  • ERRgamma
  • myocyte enhancer factor 2 (MEF2) family and USF2
  • TRAP/Mediator, through the PPARgamma-interacting subunit . TRAP220
  • PXR and HNF-4
  • SIRT1
  • leucine-rich protein 130 kDa,
  • PPARGC1A is necessary for fasting-mediated induction of CYP7A1
  • BCL3
  • SF-1 and LRH-1
  • PPARGC1A plays an important role in partitioning cytoplasmic Triglycerdes toward the VLDL secretory compartments and promoting VLDL secretion via transcriptional induction of CIDEB
  • TP53
  • RNF34
  • estrogen-related receptor (ERR) family of nuclear receptors
  • MTOR regulates mitochondrial activity through PPARGC1A and regulates glycogen levels through PKB/AKT1
  • PIAS1 interacts with PPARGC1B and affects its SUMOylation and co-activation activity
  • SENP1 is a specific SUMO protease to regulate SUMOylation status of PPARGC1A
  • PPARGC1A, PPARGC1B coactivators regulate MITF and the tanning response
  • MITF is a target of BRAF, directly regulating the expression of PPARGC1A
  • neuronal FNDC5 gene expression is regulated by PPARGC1A
  • rapid and dynamic interplay between PPARGC1A and the decorin-induced tumor suppressor gene, TCHP
  • directly interacted with BHLHE40, a basic helix-loop-helix (bHLH) transcriptional repressor induced by hypoxia, and protects skeletal muscle (SKM) from ROS damage
  • NDN is a potent PPARGC1A stabilizer that promotes mitochondrial biogenesis via PPPARGC1A in mammalian neurons
  • NRF1 together with the transcriptional co-activator PPARGC1A stimulates the expression of a broad set of nuclear genes (as COX6C) which are involved in mitochondrial biogenesis and functions
  • MAPK7 regulation of PPARGC1A is critical for cardiac mitochondrial function
  • YAP1-TEAD1 signaling induces mitochondrial biogenesis in endothelial cells (ECs) and stimulates angiogenesis through PPARGC1A
  • cell & other
    REGULATION
    activated by by CAMK4 in myocytes and MAPKs(p38) activity displacing the repressor and recruiting it to sites of transcription
    p38 MAP kinase
    induced by CREBP during starvation
    in brown adipose tissue in response to cold or obesity
    SIRT1
    in muscle by exercise and stimulates many of the best-known beneficial effects of exercise in muscle: mitochondrial biogenesis, angiogenesis and fibre-type switching
    repressed by mutant Huntingtin by associating with the promoter and interfering with the CREB/TAF4-dependent transcriptional pathway
    ZNF746
    myb binding protein, p160MBP
    Other central target of the insulin-cAMP axis in liver
    regulated by insulin, partly via FKHR binding
    negatively regulated by SCF(Cdc4)
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --low  
    in breast carcinoma with poor outcome
    constitutional     --low  
    in type 2 diabetes
    constitutional     --over  
    increased muscle expression of PPARGC1A paradoxically exacerbated fat-induced insulin resistance in skeletal muscle despite an increase in mitochondrial density and mitochondrial activity
    constitutional     --low  
    in muscle from HD subjects (
    Susceptibility
  • insulin sensitivity and non-insulin dependent diabetes (type 2) in some populations
  • obesity in middle aged women
  • Variant & Polymorphism SNP G482S polymorphism and other in insulin sensitivity, diabetes, obesity and hypertension
    Candidate gene
    Marker
    Therapy target
  • Overexpression of PGC-1 in CREB-deficient mice restored glucose homeostasis and rescued expression of gluconeogenic gene
  • SystemTypeDisorderPubmed
    neurologyneurodegenerativehuntington chorea
    activator of PPARGC1A and TFAM may be a potential therapeutic strategy in Huntington disease
    neurologyneurodegenerative 
    therapeutic agents activating PPARGC1A, PPARGC1B would be valuable for treating neurodegenerative diseases in which mitochondrial dysfunction and oxidative damage play an important pathogenic role
    cardiovascularaquired 
    beneficial role of PPARGC1A in therapies for cardiac diseases
    neurologyneurodegenerativealzheimer
    over-expression of PGC-1α could completely rescue mitochondrial biogenesis AD-causing amyloid precursor protein M17 cells
    cardiovascularaquiredheart failure
    elevating PGC-1alpha activity may have therapeutic potential in the treatment of heart failure
    neurologyneurodegenerativehuntington chorea
    PPARGC1A upstream of TFEB are important therapeutic targets in HD and potentially other neurodegenerative disorders caused by protein misfolding
    ANIMAL & CELL MODELS
  • PGC-1alpha null mice are lean and resistant to diet-induced obesity, constitutively activate gluconeogenic gene expression, and have elevated C/EBPbeta in liver
  • transverse aortic constriction in mice lacking PGC-1alpha leads to accelerated cardiac dysfunction accompanied by signs of significant clinical heart failure
  • mice lacking PGC-1alpha show abnormal diurnal rhythms of activity, body temperature and metabolic rate
  • mice with combined deficiency of PGC-1alpha and PGC-1beta died shortly after birth with small hearts, bradycardia, intermittent heart block, and a markedly reduced cardiac output
  • impaired function of PGC-1alpha plays a critical role in muscle dysfunction in Huntington's disease transgenic mice
  • expression levels of PGC-1 alpha is significantly decreased in both Alzheimer's disease hippocampal tissues and AD-causing amyloid precursor protein mutant M17 cells
  • knockdown of PGC-1 alpha could exacerbate impaired mitochondrial biogenesis and mitochondrial deficits in AD-causing amyloid precursor protein mutant M17 cells
  • mice that lack cardiac PGC-1 alpha, a powerful regulator of angiogenesis, develop profound peripartum cardiomyopathy