Search results for PPARG

Showing 23 results out of 108

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Protein (4 results from a total of 10)

Identifier: R-HSA-446172
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: PPARG: P37231
Identifier: R-HSA-4717444
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: PPARG: P37231
Identifier: R-HSA-9841933
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: PPARG: P37231
Identifier: R-HSA-9841931
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: PPARG: P37231

Reaction (4 results from a total of 41)

Identifier: R-HSA-9732629
Species: Homo sapiens
Compartment: nucleoplasm
Peroxisome proliferator-activated receptor gamma (PPARG) is expressed mainly in fat tissue, where it regulates genes involved in fat cell (adipocyte) differentiation, fatty acid uptake and storage, and glucose uptake. PPARG is a nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, PPARG binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes. PPARG can regulate peroxisomal fatty acid beta-oxidation, adipocyte differentiation and glucose homeostasis.

Thiazolidinediones (TZDs, glitazones) are a family of drugs acting as insulin sensitizers and are only approved for the treatment of type 2 diabetes mellitus (T2DM). TZDs are PPARG agonists and act via PPARG to make cells more responsive to insulin. TZDs used to manage T2DM are rosiglitazone (Henke et al. 1998, Young et al. 1998), pioglitazone (Sakamoto et al. 2000) and troglitazone (Henke et al. 1998). Troglitazone was withdrawn in 2000 due to risk of hepatotoxicity (Graham et al. 2001) but has since been extensively studied using a variety of in vivo, in vitro and computational methods (Kassahun et al. 2001).
Identifier: R-HSA-381283
Species: Homo sapiens
Compartment: nucleoplasm
As inferred from mouse homologs, ZNF467 (ZFP467) binds the promoter of the PPARG gene and recruits a histone deacetylase complex to activate transcription of PPARG.
Activation of PPARG transcription by CEPBA is inferred from mouse.
As inferred from mouse, NF-kappaB inhibits expression of PPARG in pre-adipocytes (Chae and Kwak 2003). TNFalpha represses PPARG via NF-kappaB (Chae and Kwak 2003, Kurebayashi et al. 2001, Xing et al. 1997).
The transcription factors CEBPB, CEBPD, and KLF5 simultaneously bind the PPARG promoter and synergistically activate transcription of the PPARG gene. These three factors activate transcription after initial stimulation of adipocyte differentiation but then are replaced by CEBPA within 10 days. CEBPA and other factors may be responsible for long term maintenance of PPARG expression and the differentiated state.
Pre-adipose tissue contains both the widely expressed PPARG isoform 1 mRNA and the more tissue-specific PPARG isoform 2. The PPARG isoform 2 mRNA is translated to yield PPARG isoform 2 protein, which has 505 amino acid residues (57 KDa) and is the longest of the 4 observed variants. Isoform 2 is specific to preadipose and adipose tissue (Mukherjee et al. 1997). Confusingly, the longest variant is called isoform 1 in some publications.
In mouse, by 10 days after induction of adipocyte differentiation Cebpa, but neither Cebpb nor Cebpd, is detectable at the Pparg promoter. While adipocyte differentiation can proceed without Cebpa, adipocytes differentiated from Cebpa-knockout cells are insulin insensitive due to a defect in Glut4 (Slc2a4) vesicle trafficking.
The adipogenesis regulatory factor (ADIRF, aka AFRO, APM2, C10orf116) promotes adipogenic differentiation and stimulates transcription initiation of master adipogenesis factors like PPARG and CEBPA (Ni et al. 2013).
As inferred from mouse, SREBP1A and SREBP2 bind to the PPARG1 and PPARG2 promoters and activate transcription.
As inferred from mouse, TGF-beta inhibits expression of PPARG.
ZNF638 cooperates together with CEBPB and CEBPD at the promoter of the PPARG gene to activate transcription (inferred from mouse homologs).
As inferred from mouse 3T3-L1 cells, Wnt-1 and Wnt-10b inhibit PPARG expression (Ross et al. 2000, Bennett et al. 2002) by activating COUP-TFII (NR2F2) which recruits the SMRT repressor complex to the PPARG gene (Okamura et al. 2009).
Identifier: R-HSA-4717461
Species: Homo sapiens
Compartment: nucleoplasm
As inferred from mouse homologs, PIAS1,2-2 SUMOylate PPARG with SUMO1 at lysine-107 and lysine-395 (lysine-77 and lysine-365 of the shorter variant 1). SUMOylation decreases the transcriptional activation activity of PPARG. SUMOylation at lysine-395 is ligand-dependent and causes PPARG to recruit corepressors such as NCOR and HDAC3.
Identifier: R-HSA-381290
Species: Homo sapiens
Compartment: nucleoplasm
The PPARG:RXRA heterodimer binds specific the PPRE element, two 6-bp DR-1 motifs separated by 1 nucleotide, in the promoters of target genes such as aP2/FABP4 even in the absence of fatty acid ligands that activate PPARG. When activating ligands of PPARG are absent PPARG:RXRA recruits corepressors such as NCoR2(SMRT), NCoR, and HDAC3 to maintain the target gene in an inactive state.

DNA Sequence (2 results from a total of 2)

Identifier: R-HSA-5640205
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: ENSEMBL: ENSEMBL:ENSG00000132170
Identifier: R-HSA-4686147
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: ENSEMBL: ENSEMBL:ENSG00000109189

Set (4 results from a total of 18)

Identifier: R-ALL-381235
Compartment: nucleoplasm
Identifier: R-ALL-9732650
Compartment: nucleoplasm
Identifier: R-ALL-9844666
Compartment: nucleoplasm
Identifier: R-HSA-1592227
Species: Homo sapiens
Compartment: nucleoplasm

Complex (4 results from a total of 27)

Identifier: R-HSA-2026090
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-9017458
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-9623234
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-381367
Species: Homo sapiens
Compartment: nucleoplasm

Pathway (4 results from a total of 9)

Identifier: R-HSA-2151209
Species: Homo sapiens
Compartment: nucleoplasm
The transcriptional coactivator PPARGC1A (PGC-1alpha), one of the master regulators of mitochondrial biogenesis, is activated by phosphorylation. Energy depletion causes a reduction in ATP and an increase in AMP which activates AMPK. AMPK in turn phosphorylates PPARGC1A. Likewise, p38 MAPK is activated by muscle contraction (possibly via calcium and CaMKII) and phosphorylates PPARGC1A. PPARGC1A does not bind DNA directly, but rather interacts with other transcription factors. Deacetylation of PPARGC1A by SIRT1 appears to follow phosphorylation however the role of deacetylation is unresolved (Canto et al. 2009, Gurd et al. 2011, Philp et al. 2011)
Identifier: R-HSA-381340
Species: Homo sapiens
Compartment: nucleoplasm, cytosol, plasma membrane
Adipogenesis is the process of cell differentiation by which preadipocytes become adipocytes. During this process the preadipocytes cease to proliferate, begin to accumulate lipid droplets and develop morphologic and biochemical characteristics of mature adipocytes such as hormone responsive lipogenenic and lipolytic programs. The most intensively studied model system for adipogenesis is differentiation of the mouse 3T3-L1 preadipocyte cell line by an induction cocktail of containing mitogens (insulin/IGF1), glucocorticoid (dexamethasone), an inducer of cAMP (IBMX), and fetal serum (Cao et al. 1991, reviewed in Farmer 2006). More recently additional cellular models have become available to study adipogenesis that involve almost all stages of development (reviewed in Rosen and MacDougald 2006). In vivo knockout mice lacking putative adipogenic factors have also been extensively studied. Human pathways are traditionally inferred from those discovered in mouse but are now beginning to be validated in cellular models derived from human adipose progenitors (Fischer-Posovszky et al. 2008, Wdziekonski et al. 2011).
Adipogenesis is controlled by a cascade of transcription factors (Yeh et al. 1995, reviewed in Farmer 2006, Gesta et al. 2007). One of the first observable events during adipocyte differentiation is a transient increase in expression of the CEBPB (CCAAT/Enhancer Binding Protein Beta, C/EBPB) and CEBPD (C/EBPD) transcription factors (Cao et al. 1991, reviewed in Lane et al. 1999). This occurs prior to the accumulation of lipid droplets. However, it is the subsequent inductions of CEBPA and PPARG that are critical for morphological, biochemical and functional adipocytes.
Ectopic expression of CEBPB alone is capable of inducing substantial adipocyte differentiation in fibroblasts while CEBPD has a minimal effect. CEBPB is upregulated in response to intracellular cAMP (possibly via pCREB) and serum mitogens (possibly via Krox20). CEBPD is upregulated in response to glucocorticoids. The exact mechanisms that upregulate the CEBPs are not fully known.
CEBPB and CEBPD act directly on the Peroxisome Proliferator-activated Receptor Gamma (PPARG) gene by binding its promoter and activating transcription. CEBPB and CEBPD also directly activate the EBF1 gene (and possibly other EBFs) and KLF5 (Jimenez et al. 2007, Oishi 2005). The EBF1 and KLF5 proteins, in turn bind, and activate the PPARG promoter. Other hormones, such as insulin, affect PPARG expression and other transcription factors, such as ADD1/SREBP1c, bind the PPARG promoter. This is an area of ongoing research.
During adipogenesis the PPARG gene is transcribed to yield 2 variants. The adipogenic variant 2 mRNA encodes 30 additional amino acids at the N-terminus compared to the widely expressed variant 1 mRNA.
PPARG encodes a type II nuclear hormone receptor (remains in the nucleus in the absence of ligand) that forms a heterodimer with the Retinoid X Receptor Alpha (RXRA). The heterodimer was initially identified as a complex regulating the aP2/FABP4 gene and named ARF6 (Tontonoz et al. 1994).
The PPARG:RXRA heterodimer binds a recognition sequence that consists of two hexanucleotide motifs (DR1 motifs) separated by 1 nucleotide. Binding occurs even in the absence of ligands, such as fatty acids, that activate PPARG. In the absence of activating ligands, the PPARG:RXRA complex recruits repressors of transcription such as SMRT/NCoR2, NCoR1, and HDAC3 (Tontonoz and Spiegelman 2008).
Each molecule of PPARG can bind 2 molecules of activating ligands. Although, the identity of the endogenous ligands of PPARG is unknown, exogenous activators include fatty acids and the thiazolidinedione class of antidiabetic drugs (reviewed in Berger et al. 2005, Heikkinen et al. 2007, Lemberger et al. 1996). The most potent activators of PPARG in vitro are oxidized derivatives of unsaturated fatty acids.. Upon binding activating ligands PPARG causes a rearrangement of adjacent factors: Corepressors such as SMRT/NCoR2 are lost and coactivators such as TIF2, PRIP, CBP, and p300 are recruited (Tontonoz and Spiegelman). PPARG also binds directly to the TRAP220 subunit of the TRAP/Mediator complex that recruits RNA polymerase II. Thus binding of activating ligand by PPARG causes transcription of PPARG target genes.
Targets of PPARG include genes involved in differentiation (PGAR/HFARP, Perilipin, aP2/FABP4, CEBPA), fatty acid transport (LPL, FAT/CD36), carbohydrate metabolism (PEPCK-C, AQP7, GK, GLUT4 (SLC2A4)), and energy homeostasis (LEPTIN and ADIPONECTIN) (Perera et al. 2006).
Within 10 days of differentiation CEBPB and CEBPD are no longer located at the PPARG promoter. Instead CEBPA is present. EBF1 and PPARG bind the CEBPA promoter and activate transcription of CEBPA, one of the key transcription factors in adipogenesis. A current hypothesis posits a self-reinforcing loop that maintains PPARG expression and the differentiated state: PPARG activates CEBPA and CEBPA activates PPARG. Additionally EBF1 (and possibly other EBFs) activates CEBPA, CEBPA activates EBF1, and EBF1 activates PPARG.
Identifier: R-HSA-9022707
Species: Homo sapiens
MECP2 regulates transcription of several transcription factors involved in functioning of the nervous system, such as CREB1, MEF2C, RBFOX1 (Chahrour et al. 2008) and PPARG (Mann et al. 2010, Joss Moore et al. 2011).
Identifier: R-HSA-8943724
Species: Homo sapiens
Transcription of the PTEN gene is regulated at multiple levels. Epigenetic repression involves the recruitment of Mi-2/NuRD upon SALL4 binding to the PTEN promoter (Yang et al. 2008, Lu et al. 2009) or EVI1-mediated recruitment of the polycomb repressor complex (PRC) to the PTEN promoter (Song et al. 2009, Yoshimi et al. 2011). Transcriptional regulation is also elicited by negative regulators, including NR2E1:ATN1 (atrophin-1) complex, JUN (c-Jun), SNAIL and SLUG (Zhang et al. 2006, Vasudevan et al. 2007, Escriva et al. 2008, Uygur et al. 2015) and positive regulators such as TP53 (p53), MAF1, ATF2, EGR1 or PPARG (Stambolic et al. 2001, Virolle et al. 2001, Patel et al. 2001, Shen et al. 2006, Li et al. 2016).

Icon (1 results from a total of 1)

Species: Homo sapiens
Curator: Bruce May
Designer: Cristoffer Sevilla
PPARG icon
Peroxisome proliferator-activated receptor gamma
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