Peroxisome proliferator-activated receptor gamma

Peroxisome proliferator-activated receptor gamma (PPAR-γ or PPARG), also known as the glitazone reverse insulin resistance receptor, or NR1C3 (nuclear receptor subfamily 1, group C, member 3) is a type II nuclear receptor functioning as a transcription factor that in humans is encoded by the PPARG gene.^[5][6][7]

PPARG
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1FM6, 1FM9, 1I7I, 1K74, 1KNU, 1NYX, 1PRG, 1RDT, 1WM0, 1ZEO, 1ZGY, 2ATH, 2F4B, 2FVJ, 2G0G, 2G0H, 2GTK, 2HFP, 2HWQ, 2HWR, 2I4J, 2I4P, 2I4Z, 2OM9, 2P4Y, 2POB, 2PRG, 2Q59, 2Q5P, 2Q5S, 2Q61, 2Q6R, 2Q6S, 2Q8S, 2QMV, 2VSR, 2VST, 2VV0, 2VV1, 2VV2, 2VV3, 2VV4, 2XKW, 2YFE, 2ZK0, 2ZK1, 2ZK2, 2ZK3, 2ZK4, 2ZK5, 2ZK6, 2ZNO, 2ZVT, 3ADS, 3ADT, 3ADU, 3ADV, 3ADW, 3ADX, 3AN3, 3AN4, 3B0Q, 3B0R, 3B1M, 3B3K, 3BC5, 3CDP, 3CDS, 3CS8, 3CWD, 3D6D, 3DZU, 3DZY, 3E00, 3ET0, 3ET3, 3FEJ, 3FUR, 3G9E, 3GBK, 3H0A, 3HO0, 3HOD, 3IA6, 3K8S, 3KMG, 3LMP, 3NOA, 3OSI, 3OSW, 3PBA, 3PO9, 3PRG, 3QT0, 3R5N, 3R8A, 3R8I, 3S9S, 3SZ1, 3T03, 3TY0, 3U9Q, 3V9T, 3V9V, 3V9Y, 3VJH, 3VJI, 3VN2, 3VSO, 3VSP, 3WJ4, 3WJ5, 3WMH, 3X1H, 3X1I, 4A4V, 4A4W, 4CI5, 4E4K, 4E4Q, 4EM9, 4EMA, 4F9M, 4FGY, 4HEE, 4JAZ, 4JL4, 4L96, 4L98, 4O8F, 4OJ4, 4PRG, 4PVU, 4PWL, 4R2U, 4R6S, 4XLD, 4R06, 4Y29, 4XTA, 4XUM, 4YT1, 4XUH, 5F9B, 5AZV
Identifiers
Aliases	PPARG, CIMT1, GLM1, NR1C3, PPARG1, PPARG2, PPARgamma, peroxisome proliferator activated receptor gamma, PPARG5
External IDs	OMIM: 601487 MGI: 97747 HomoloGene: 7899 GeneCards: PPARG
Gene location (Human) Chr. Chromosome 3 (human)^[1] Band 3p25.2 Start 12,287,368 bp^[1] End 12,434,356 bp^[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)^[2] Band 6 E3|6 53.41 cM Start 115,337,912 bp^[2] End 115,467,360 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in subcutaneous adipose tissue rectum right lung urinary bladder Achilles tendon jejunal mucosa placenta upper lobe of left lung body of stomach right lobe of thyroid gland Top expressed in brown adipose tissue white adipose tissue mucous cell of stomach subcutaneous adipose tissue epithelium of stomach pyloric antrum secondary oocyte mammary gland cumulus cell intercostal muscle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding alpha-actinin binding chromatin binding prostaglandin receptor activity core promoter sequence-specific DNA binding enzyme binding protein phosphatase binding metal ion binding arachidonic acid binding nuclear receptor coactivator activity steroid hormone receptor activity sequence-specific DNA binding identical protein binding nuclear receptor activity DNA-binding transcription factor activity DNA binding double-stranded DNA binding protein C-terminus binding zinc ion binding peptide binding protein self-association retinoid X receptor binding protein heterodimerization activity DNA binding domain binding LBD domain binding DNA-binding transcription factor activity, RNA polymerase II-specific transcription factor binding estrogen receptor binding E-box binding transcription cis-regulatory region binding RNA polymerase II transcription regulatory region sequence-specific DNA binding DNA-binding transcription repressor activity, RNA polymerase II-specific fatty acid binding lipid binding signaling receptor activity Cellular component cytosol RNA polymerase II transcription regulator complex perinuclear region of cytoplasm cytoplasm nucleus intracellular membrane-bounded organelle nucleoplasm protein-containing complex Biological process negative regulation of cell population proliferation epithelial cell differentiation negative regulation of smooth muscle cell proliferation positive regulation of oligodendrocyte differentiation transcription, DNA-templated activation of cysteine-type endopeptidase activity involved in apoptotic process response to lipid placenta development cellular response to vitamin E negative regulation of interferon-gamma-mediated signaling pathway negative regulation of sequestering of triglyceride regulation of fat cell differentiation cellular response to retinoic acid glucose homeostasis negative regulation of collagen biosynthetic process cellular response to hyperoxia response to estrogen regulation of cholesterol transporter activity regulation of circadian rhythm negative regulation of telomerase activity signal transduction cellular response to insulin stimulus monocyte differentiation regulation of transcription by RNA polymerase II regulation of blood pressure positive regulation of apoptotic process positive regulation of fat cell differentiation negative regulation of cholesterol storage regulation of transcription, DNA-templated negative regulation of cell growth negative regulation of transcription, DNA-templated cellular response to prostaglandin stimulus animal organ regeneration positive regulation of DNA-binding transcription factor activity lipoprotein transport response to metformin heart development response to cold negative regulation of acute inflammatory response fatty acid oxidation lipid homeostasis transcription initiation from RNA polymerase II promoter response to vitamin A innate immune response response to retinoic acid cell maturation cell fate commitment peroxisome proliferator activated receptor signaling pathway rhythmic process response to mechanical stimulus long-chain fatty acid transport lipid metabolism response to caffeine positive regulation of fatty acid oxidation response to immobilization stress positive regulation of phagocytosis, engulfment negative regulation of pancreatic stellate cell proliferation response to starvation response to organic cyclic compound regulation of lipid metabolic process steroid hormone mediated signaling pathway response to organic substance response to nutrient cellular response to prostaglandin E stimulus negative regulation of transcription by RNA polymerase II white fat cell differentiation negative regulation of macrophage derived foam cell differentiation positive regulation of transcription by RNA polymerase II G protein-coupled receptor signaling pathway macrophage derived foam cell differentiation positive regulation of DNA binding positive regulation of transcription, DNA-templated negative regulation of angiogenesis negative regulation of blood vessel endothelial cell migration pri-miRNA transcription by RNA polymerase II negative regulation of gene silencing by miRNA cellular response to low-density lipoprotein particle stimulus positive regulation of vascular associated smooth muscle cell apoptotic process negative regulation of vascular endothelial cell proliferation negative regulation of vascular associated smooth muscle cell proliferation fatty acid metabolic process multicellular organism development hormone-mediated signaling pathway cell differentiation intracellular receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5468 19016 Ensembl ENSG00000132170 ENSMUSG00000000440 UniProt P37231 P37238 RefSeq (mRNA) NM_005037 NM_015869 NM_138711 NM_138712 NM_001330615 NM_001354666 NM_001354667 NM_001354668 NM_001354669 NM_001354670 NM_001374261 NM_001374262 NM_001374263 NM_001374264 NM_001374265 NM_001374266 NM_001127330 NM_011146 NM_001308352 NM_001308354 RefSeq (protein) NP_001317544 NP_005028 NP_056953 NP_619725 NP_619726 NP_001341595 NP_001341596 NP_001341597 NP_001341598 NP_001341599 NP_001361190 NP_001361191 NP_001361192 NP_001361193 NP_001361194 NP_001361195 NP_001120802 NP_001295281 NP_001295283 NP_035276 Location (UCSC) Chr 3: 12.29 – 12.43 Mb Chr 6: 115.34 – 115.47 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

Tissue distribution

PPARG is mainly present in adipose tissue, colon and macrophages. Two isoforms of PPARG are detected in the human and in the mouse: PPAR-γ1 (found in nearly all tissues except muscle) and PPAR-γ2 (mostly found in adipose tissue and the intestine).^[8][9]

Gene expression

This gene encodes a member of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear receptors. PPARs form heterodimers with retinoid X receptors (RXRs) and these heterodimers regulate transcription of various genes. Three subtypes of PPARs are known: PPAR-alpha, PPAR-delta, and PPAR-gamma. The protein encoded by this gene is PPAR-gamma and is a regulator of adipocyte differentiation. Alternatively spliced transcript variants that encode different isoforms have been described.^[10]

The activity of PPARG can be regulated via phosphorylation through the MEK/ERK pathway. This modification decreases transcriptional activity of PPARG and leads to diabetic gene modifications, and results in insulin insensitivity. For example, the phosphorylation of serine 112 will inhibit PPARG function, and enhance adipogenic potential of fibroblasts.^[11]

Function

PPARG regulates fatty acid storage and glucose metabolism. The genes activated by PPARG stimulate lipid uptake and adipogenesis by fat cells. PPARG knockout mice are devoid of adipose tissue, establishing PPARG as a master regulator of adipocyte differentiation.^[12]

PPARG increases insulin sensitivity by enhancing storage of fatty acids in fat cells (reducing lipotoxicity), by enhancing adiponectin release from fat cells, by inducing FGF21,^[12] and by enhancing nicotinic acid adenine dinucleotide phosphate production through upregulation of the CD38 enzyme.^[13]

PPARG promotes anti-inflammatory M2 macrophage activation in mice.^[14]

Adiponectin induces ABCA1-mediated reverse cholesterol transport by activation of PPAR-γ and LXRα/β.^[15]

Many naturally occurring agents directly bind with and activate PPAR gamma. These agents include various polyunsaturated fatty acids like arachidonic acid and arachidonic acid metabolites such as certain members of the 5-hydroxyicosatetraenoic acid and 5-oxo-eicosatetraenoic acid family, e.g., 5-oxo-15(S)-HETE and 5-oxo-ETE or 15-hydroxyicosatetraenoic acid family including 15(S)-HETE, 15(R)-HETE, and 15(S)-HpETE,^[16][17][18] the phytocannabinoid tetrahydrocannabinol (THC),^[19] its metabolite THC-COOH, and its synthetic analog ajulemic acid (AJA).^[20] The activation of PPAR gamma by these and other ligands may be responsible for inhibiting the growth of cultured human breast, gastric, lung, prostate and other cancer cell lines.^[21][22]

During embryogenesis, PPARG first substantially expresses in interscapular brown fat pad.^[23] The depletion of PPARG will result in embryonic lethality at E10.5, due to the vascular anomalies in placenta, with no permeation of fetal blood vessels and dilation and rupture of maternal blood sinuses.^[24] The expression PPARG can be detected in placenta as early as E8.5 and through the remainder of gestation, mainly located in the primary trophoblast cell in the human placenta.^[23] PPARG is required for epithelial differentiation of trophoblast tissue, which is critical for proper placenta vascularization. PPARG agonists inhibit extravillous cytotrophoblast invasion. PPARG is also required for the accumulation of lipid droplets by the placenta.^[11]

Interactions

Peroxisome proliferator-activated receptor gamma has been shown to interact with:

• Tetrahydrocannabivarin
• Cannabidiol
• Anandamide
• CD36^[14]
• EDF1^[25][26][27]
• EP300^[28][29]
• HDAC3^[28][30]
• MED1^[29]
• NCOA3^[29]
• NCOA4^[31]
• NCOA2^[29]
• NR0B2^[32]
• PPARGC1A^[33][34]
• RB1.^[28]
• miR3666^[35]

Research

PPAR-gamma agonists have been used in the treatment of hyperlipidaemia and hyperglycemia.^[36][37]

Many insulin sensitizing drugs (namely, the thiazolidinediones) used in the treatment of diabetes activate PPARG as a means to lower serum glucose without increasing pancreatic insulin secretion. Activation of PPARG is more effective for skeletal muscle insulin resistance than for insulin resistance of the liver.^[38]

See also

• Endocannabinoid system
• Endocannainoidome

References

1. GRCh38: Ensembl release 89: ENSG00000132170 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000000440 - Ensembl, May 2017
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4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.