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FLASH GENE
Symbol PPARG contributors: mct/shn - updated : 12-01-2017
HGNC name peroxisome proliferative-activated receptor, gamma
HGNC id 9236
Corresponding disease
DIDAN insulin dependent diabetes mellitus with acanthosis nigricans
FPLD3 familial partial lipodystrophy, 3, Dunnigan type
PPARG marked obesity
Location 3p25.2      Physical location : 12.329.348 - 12.475.854
Synonym name
  • nuclear receptor subfamily 1 group C member 3
  • PPAR gamma
  • PPAR-gamma
  • peroxisome proliferative-activated receptor, gamma
  • peroxisome proliferator-activated nuclear receptor gamma variant 1
  • Synonym symbol(s) NR1C3, PPARG1, PPARG2, PPARgamma, CIMT1, GLM1
    DNA
    TYPE functioning gene
    STRUCTURE 146.51 kb     8 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site   transcription factor
    text structure
  • promoter with responsive element for ROR alpha (RORE) and STAT1 binding site
  • two KLF9-binding sites within the 0.6-kb region of the PPARG proximal promoter
  • MAPPING cloned Y linked Y status confirmed
    Map pter - D3S3714 - D3S1259 - PPARG PPARG - D3S3701 - D3S3693 - cen
    Text [PPARG ]
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    8 splicing 1892 - 477 - 1997 9030579
    exons A1, A2
    7 splicing 1818 - 477 adipose tissues, intestine, neutrophils and peripheral blood lymphocytes£less abundant than G1 1997 9030579
    exon B
    8 initiation site 1919 - 477 - 1997 9030579
    7 splicing 1820 - 505 adipocytes 1997 9030579
  • additional 30 AA at the N-terminus that render its ligand-independent activation domain ,which is more effective in activating the transcription of the PPARG reporter gene
  • involved in the adipose tissue development and insulin sensitivity
  • EXPRESSION
    Type
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinelarge intestine   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Lymphoid/Immunemacrophage
    not specificadipocyte Homo sapiens
    cell lineage adipocytes
    cell lines
    fluid/secretion
    at STAGE
    physiological period pregnancy
    Text placenta, in the diploid trophoblast lineages for the isoform 1 and required for placental development
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • DNA-binding and ligand-binding domains (LBD) linked to divergent N terminal regions, with a role for helix 7 of the LBD in regulating adipocyte function
  • mono polymer heteromer , dimer
    HOMOLOGY
    interspecies ortholog to Pparg, Mus musculus
    ortholog to pparg, Danio rerio
    ortholog to Pparg, Rattus norvegicus
    ortholog to PPARG, Pan troglodytes
    Homologene
    FAMILY
  • nuclear hormone receptor family
  • NR1 subfamily
  • CATEGORY receptor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,nucleus
    text
  • PPARG colocalized with vimentin in certain organelles, i.e. Golgi, mitochondria and endoplasmic reticulum
  • basic FUNCTION
  • modulator of insulin sensitivity and control of glucose homeostasis and blood pressure and activation of antidiabetic effect of thiazolidinediones
  • regulates transcription in response to prostanoid and thiazolidinedione ligands and promotes adipocyte differentiation
  • implicated in transcriptional activation, modulated by growth factor or cytokine-stimulated signal transduction pathways involved in adipogenesis
  • a critical physiological role for PPAR gamma function in beta-cell proliferation
  • regulates diverse lipid and glucose homeostasis
  • a critical role in blood pressure regulation
  • key regulator of adipose cell differentiation, fatty acid uptake and lipogenesis
  • negative regulator of macrophage activation, inhibiting production of monocyte inflammatory cytokines and regulating both native and acquired immune responses
  • jointly required for full adipocyte differentiation and fat deposition with variability influencing plasma leptin levels in obese humans
  • increasing PAI1 expression in endothelial cells
  • activation of PPARG inhibits osteocalcin expression both by suppressing the expression of RUNX2 and by interfering with the transactivation ability of RUNX2
  • inducing acute hepatic steatosis while markedly decreasing peripheral adiposity
  • activates the IL8RB promoter by binding to a PPAR response element (PPRE)
  • key negative regulator of T helper cells secreting interleukin (IL)-17 differentiation
  • prime inducer of adipogenesis that inhibits osteoblastogenesis
  • participates in the insulin-induced Insulin-degrading enzyme expression in neurons
  • role for central nervous system PPARG in the regulation of energy balance
  • played a crucial role in the SERPINF1-mediated induction of TNFSF10 in macrophages
  • directly regulates the MGAT1 promoter activity
  • increased PPARG and MGAT1 activity during a high-fat diet (HFD) plays a major role in developing hepatic steatosis by regulating fatty acid transport and the triglyceride (TG) incorporation pathway
  • hepatic PPARG enhances lipid accumulation in liver mainly through the up-regulation of adipogenic genes
  • acts as an E3 ubiquitin ligase, physically interacting with RELA to induce its ubiquitination and degradation
  • key role of PPARG in regulating pancreatic beta-cell function by improving the stability of PDX1 and MAFA proteins
  • induces MUC1 ubiquitination and degradation that is critical to terminate MUC1 signaling pathway-elicited cancer
  • MKL1 and PPARG act in a mutually antagonistic manner in the adipocytic differentiation programme
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS adipogenesis
    text adipogenesis and lipogenesis
    PATHWAY
    metabolism energetic
    signaling hormonal
    a component
  • heterodimerizing with RXR
  • PPARG-FGF1 axis is critical for maintaining metabolic homeostasis and insulin sensitization
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • ARA70
  • 9-cis-retinoic acid receptor (RXR) heterodimers
  • RXRalpha
  • NF-E2-related factor 2, NRF2
  • SRC-1, TIF2, AIB-1, p300, TRAP220/DRIP205
  • DRIP205 and p160
  • liver fatty acid binding protein, L-FABP
  • Multiprotein bridging factor, MBF-1
  • FKHR
  • centrosome-associated protein CAP350
  • Breast cancer amplified sequence 2, BCAS2
  • PPARgamma-DBD-interacting protein 1, PDIP1-alpha
  • HIV-1 Tat-interacting protein 60, Tip60
  • SFRS1
  • CDX1 and CEBPA
  • FGF21
  • insulin receptor, IR
  • Sp1
  • regulatory functions of AEBP1 on PPARG1 and NR1H3 transcriptional activity in the context of macrophage cholesterol homeostasis and inflammation
  • APMAP
  • histone deacetylase 4, HDAC4
  • LPIN1 phosphatidic acid phosphatase activity, but not its coactivator activity, is required for induction of PPARG
  • DICER1 might have important roles in the expression of adipogenic genes including PPARG and CEBPA via regulation of the expression of miRNAs at the early, but not the late, stage of adipocyte differentiation
  • STK3/STK4 timulated the binding of SAV1 to PPARG, a transcription factor that plays a key role in adipogenesis
  • inhibits airway epithelial cell inflammatory response through a MUC1-dependent mechanism
  • PPARG may be an important TBX20 co-factor activating energy metabolism genes in the adult heart while REST, a known transcriptional repressor, may act with TBX20 to silence genes controlling genetic programs unrelated to adult heart function
  • metabolic role for FGF1 as a critical transducer of PPARG signalling that mediates the proper coupling of nutrient storage to adaptive remodelling of adipose tissue
  • blocks likely adipogenesis by reinforcing HDAC1 recruitment to the PPARG promoter, and is one of the mediators that reset the pattern of PPARG expression in response to hypoxia
  • PPARG activation contributes to the regulation of ceramide metabolism during adipogenesis via FAM57B
  • regulatory cascade containing PPARG and TWIST1 that controlled the expression of GPS2 and NCOR2 in human adipocytes
  • PPARG may contribute to the constitutive expression of LPIN1 in adipocyte, and activation of PPARG can alleviate the suppression of LPIN1 expression by ER stress
  • TAF7L is required for activating adipocyte-specific genes via a dual mechanism wherein it interacts with PPARG at enhancers and TBP/Pol II at core promoters
  • is a novel target gene of PPARG (upregulation of FAM3A by PPARG activation is correlated with increased AKT1 level in liver cells)
  • LPIN1 functions as a key regulator of PPARG activity through its ability to release co-repressors and recruit co-activators via a mechanism other than PPARA activation
  • coordinate interaction between PTGES and PPARG is required for white-to-brown fat conversion
  • is required for transcriptional activation of the MRAP gene during adipogenesis, which contributes to understanding of the molecular mechanism of lipolysis in adipocytes
  • transcription of LIPE is regulated by the PPARG/MRAP-mediated signaling pathway
  • PPARG, an E3 ubiquitin ligase, is an inhibitor of MUC1-mediated cell proliferation
  • suppression of PPARG by FABP4 in visceral fat may explain the reported role of FABP4 in the development of obesity-related morbidities, including insulin resistance, diabetes, and atherosclerosis
  • GATA2 mediated leptin inhibition of PPARG expression by its binding site in PPARG promoter in Hepatic stellate cell (HSC) and GATA2 promoted HSC activation
  • ATF3-mediated inhibition of PPARG expression may contribute to inhibition of adipocyte differentiation during cellular stress including ER stress
  • FLII binds directly to and suppresses the transcriptional activity of PPARG
  • PPARG could inhibit Hepatocellular carcinoma (HCC) cell growth via regulating the expression and blocking the oncogenic function of SEPT2
  • activation of PPARG increases, in a PPARG-dependent manner, the expression of ADTRP in human macrophages and atherosclerotic lesions
  • WNT1 regulates the expression of CD36 through TCF4 and PPARG
  • TRIM23, stabilizes PPARG protein and mediates atypical polyubiquitin conjugation
  • AJUBA recruits CREBBP via its LIM domain and facilitates CREBBP binding to PPARG
  • dual roles for JMJD6 in promoting adipogenic gene expression program by post-transcriptional regulation of CEBPB and CEBPD and direct transcriptional activation of PPARG2 and CEBPA during adipocyte differentiation
  • SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARG, CEBPA and MEST
  • ZFP36L1 overexpression might repress adipogenesis at least by down-regulating PPARG expression through post-transcriptional mechanisms
  • PPARG binds to the promoter of DLC1 gene to regulate its expression during both white and brown adipocyte differentiation
  • CACUL1 tightly regulates PPARG signaling through the mutual opposition between SIRT1 and KDM1A, providing insight into its potential use for anti-obesity treatment
  • MAGED1 bound to PPARG and suppressed the stability and transcriptional activity of PPARG
  • PIAS1 is a specific E3 ligase for PPARG SUMOylation
  • NOVA2 integrated splicing decisions in order to regulate PPPARG and E2F1 activities
  • cell & other
    REGULATION
    activated by coactivated by SRCO1
    EGR1 in vascular smooth muscle cells
    Small heterodimer partner, SHP
    induced by CEBPB and CEBPD
    inhibited by NR0B1 in a dose-dependent manner
    histone deacetylase 4, HDAC4
    repressed by STAT1 in adipocytes (transcriptional reprssion)
    Wnt pathway through CaMKII-TAK1-TAB2-NLK
    Other regulated through association with ligands that include the thiazolidinedione class of antidiabetic drugs, as well as derivatives of polyunsaturated fatty acids
    ASSOCIATED DISORDERS
    corresponding disease(s) PPARG , DIDAN , FPLD3
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   translocation    
    in thyroid follicular carcinoma: t(2;3)(q13;p25), chimeric fusion protein 5' - PAX8 - PPARG - 3'
    tumoral     --over  
    in colorectal carcinoma
    tumoral        
    is expressed in several MEN1-related tumor types, and loss of PPARG function may contribute to lipoma development in MEN1 patients
    constitutional     --low  
    leads to increased trophoblast invasion and miscarriages
    Susceptibility
  • to hypertension
  • to non insulin dependent diabetes
  • to ovarian carcinoma
  • Variant & Polymorphism SNP
  • P12A, low in renal carcinoma, and associated with decreased risk of diabetic nephropathy in type 2 diabetes
  • H449H overexpressed in ovarian carcinomas
  • P12A increases risk for diabetes in persons with impaired glucose tolerance, an effect modified by body mass index but having no effect on the beneficial response to troglitazone
  • Candidate gene
    Marker
    Therapy target
  • can protects against atherosclerosis, through stimulation of CYP27A1
  • represents a promising molecular target for specific immunointervention in Th17-mediated autoimmune diseases such as multiple sclerosis
  • SystemTypeDisorderPubmed
    cardiovascularatheroma 
    can protects against atherosclerosis, through stimulation of CYP27A1
    immunologyautoimmune 
    represents a promising molecular target for specific immunointervention in Th17-mediated autoimmune diseases such as multiple sclerosis
    metabolismlipid 
    inhibition of PPARG-induced MGAT1 for the alternative TG synthesis pathway would be one of the excellent therapeutic targets for hepatic steatosis
    cancerdigestiveliver
    PPARG could be developed as a new target for the treatment of liver cancer.
    ANIMAL & CELL MODELS
  • mouse PPAR gamma gene knockout leads to severe myocardial thinning and death by E10.0
  • Homozygous PPAR gamma-deficient embryos died at 10.5-11.5 dpc due to placental dysfunction
  • Heterozygous PPAR gamma-deficient mice showed overexpression and hypersecretion of leptin despite the smaller size of adipocytes and decreased fat mass
  • mice chimeric for wild-type and PPAR gamma null cells show little or no contribution of null cells to adipose tissue
  • PPAR-gamma(+/-) mice display no statistically significant differences in body weight, basal glucose, insulin, or FFA levels compared to wild-type
  • insulin-induced increase in glucose disposal rate was significantly increased and insulin-induced suppression of hepatic glucose production was significantly greater in the PPAR-gamma(+/-) mice
  • Pparg mutant mice exhibit impaired skin wound healing
  • deletion of the PPARgamma gene in mouse mammary epithelium and epithelial cells, B- and T-cells, and ovary does not affect mammary development and propensity for tumor formation but leads to reduced fertility
  • neither hemizygous deletion of Pparg nor complete ablation of Ppara influenced the development of prostate cancer in mouse model
  • elimination of expression of the PPARG gene in mouse beta cells leads to significant islet hyperplasia
  • knock out of Pparg in mouse skeletal muscle causes glucose intolerance and progressive insulin resistance
  • Targeted deletion of PPARgamma in adipose tissue results in marked adipocyte hypocellularity and hypertrophy, elevated levels of plasma free fatty acids and triglyceride, decreased levels of plasma leptin and ACRP30, increased hepatic glucogenesis and insulin resistance
  • in contrast to the embryonic lethality of PPARgamma1-deficient mice, PPARgamma2(-/-) mice survived but exhibited an overall reduction in white adipose tissue, less lipid accumulation, and decreased expression of adipogenic genes in adipose tissue, and impairment of insulin sensitivity
  • homozygous mice with the equivalent P465L mutation die in utero while heterozygous mice grow normally with normal total adipose tissue weight but a reduced interscapular brown adipose tissue, intra-abdominal fat mass, increased extra-abdominal subcutaneous fat, and are hypertensive
  • disruption of PPARgamma in mouse myeloid cells impairs alternative macrophage activation, and predisposes to development of diet-induced obesity, insulin resistance, and glucose intolerance
  • targeted deletion of PPAR gamma in mice results in the production of "toxic milk" containing elevated levels of inflammatory lipids
  • Tie2Cre/flox mouse model in which PPAR-gamma is deleted in osteoclasts but not in osteoblasts develop osteopetrosis characterized by increased bone mass, reduced medullary cavity space and extramedullary hematopoiesis in the spleen
  • blocking the endogenous activation of central nervous system PPARG with pharmacological antagonists or reducing its expression with shRNA leads to negative energy balance, restored leptin sensitivity in high-fat-diet rats and blocked the hyperphagic response to oral thiazolidinedione treatment
  • food intake was reduced and energy expenditure increased
  • C3H mice do not express Pparg and Mgat1 in the liver and are protected against hepatic steatosis while being fed a HFD during high-fat diet in mice with neuron-specific Pparg knockout
  • over-expression of PPARG in cultured cortical neurons protects neurons from either HDAC4 over-expression- or H(2) O(2) -induced damage
  • C3H mice do not express Pparg and Mgat1 in the liver and are protected against hepatic steatosis while being fed a high-fat diet (HFD)