Peroxisome proliferator-activated receptor gamma

Peroxisome proliferator-activated receptor gamma (PPAR-γ or PPARG), also known as the glitazone receptor, or NR1C3 (nuclear receptor subfamily 1, group C, member 3) is a type II nuclear receptor (protein regulating genes) 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 115,360,951 bp[2] End 115,490,399 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • GO:0001948 protein binding • drug binding • alpha-actinin binding • activating transcription factor binding • chromatin binding • prostaglandin receptor activity • core promoter sequence-specific DNA binding • enzyme binding • protein phosphatase binding • metal ion binding • arachidonic acid binding • ligand-dependent nuclear receptor transcription coactivator activity • steroid hormone receptor activity • sequence-specific DNA binding • identical protein binding • GO:0038050, GO:0004886, GO:0038051 nuclear receptor activity • GO:0001131, GO:0001151, GO:0001130, GO:0001204 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 • DBD domain binding • LBD domain binding • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific • transcription factor binding • estrogen receptor binding • E-box binding • transcription regulatory region sequence-specific DNA binding • RNA polymerase II regulatory region sequence-specific DNA binding • GO:0001078, GO:0001214, GO:0001206 DNA-binding transcription repressor activity, RNA polymerase II-specific • RNA polymerase II repressing transcription factor binding • fatty acid binding • lipid binding • signaling receptor activity Cellular component • cytosol • RNA polymerase II transcription factor complex • perinuclear region of cytoplasm • cytoplasm • cell nucleus • intracellular membrane-bounded organelle • nucleoplasm • macromolecular complex Biological process • negative regulation of cell 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 • negative regulation of receptor biosynthetic process • placentation • 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 from RNA polymerase II promoter • regulation of blood pressure • positive regulation of apoptotic process • low-density lipoprotein particle receptor biosynthetic process • positive regulation of fat cell differentiation • negative regulation of cholesterol storage • regulation of transcription, DNA-templated • negative regulation of cell growth • response to drug • negative regulation of transcription, DNA-templated • cellular response to prostaglandin stimulus • animal organ regeneration • positive regulation of sequence-specific 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 system • 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 transcription involved in cell fate commitment • 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 from RNA polymerase II promoter • white fat cell differentiation • negative regulation of macrophage derived foam cell differentiation • positive regulation of transcription from RNA polymerase II promoter • 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 from RNA polymerase II promoter • 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 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: 115.36 – 115.49 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 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-hydroxyicosatetraenoicacid 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]

During embryogenesis, PPARG first substantially expresses in interscapular brown fat pad.[22] 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.[23] 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.[22] 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:

• CD36[14]
• EDF1[24][25][26]
• EP300[27][28]
• HDAC3[27][29]
• MED1[28]
• NCOA3[28]
• NCOA4[30]
• NCOA2[28]
• NR0B2[31]
• PPARGC1A[32][33]
• RB1.[27]

Clinical relevance

PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis, and cancer. PPAR-gamma agonists have been used in the treatment of hyperlipidaemia and hyperglycemia.[34][35] PPAR-gamma decreases the inflammatory response of many cardiovascular cells, particularly endothelial cells.[36] PPAR-gamma activates the PON1 gene, increasing synthesis and release of paraoxonase 1 from the liver, reducing atherosclerosis.[37]

Low PPAR-gamma reduces the capacity of adipose tissue to store fat, resulting in increased storage of fat in nonadipose tissue (lipotoxicity).[38] A soy protein diet increases adipose tissue PPAR-gamma, thereby reducing lipotoxicity.[38]

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.[39] Different classes of compounds which activate PPARG weaker than thiazolidinediones (the so-called "partial agonists of PPARgamma") are currently studied with the hope that such compounds would be still effective hypoglycemic agents but with fewer side effects.[40]

The medium-chain triglyceride decanoic acid has been shown to be a partially-activating PPAR-gamma ligand that does not increase adipogenesis.[41] Activation of PPAR-gamma by decanoic acid has been shown to increase mitochondrial number, increase the mitochondrial enzyme citrate synthase, increase complex I activity in mitochondria, and increase activity of the antioxidant enzyme catalase.[42]

A fusion protein of PPAR-γ1 and the thyroid transcription factor PAX8 is present in approximately one-third of follicular thyroid carcinomas, to be specific those cancers with a chromosomal translocation of t(2;3)(q13;p25), which permits juxtaposition of portions of both genes.[43][44]

The phytocannabinoid cannabidiol (CBD) has been shown to activate PPAR gamma in in vitro and in vivo models.[45][46] The cannabinoid carboxylic acids THCA, CBDA and CBGA activate PAARy more efficient than their decarboxylated products; however, THCA was the acid found with highest activity. As a synthetic analog of THC‐COOH, the major non‐psychotropic metabolite of THC, ajulemic acid also is a potent PPARγ agonist. The carboxylic acid group is critical for a stronger and a long activation time.[47]

References

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Further reading

• Qi C, Zhu Y, Reddy JK (2001). "Peroxisome proliferator-activated receptors, coactivators, and downstream targets". Cell Biochemistry and Biophysics. 32 Spring (1–3): 187–204. doi:10.1385/cbb:32:1-3:187. PMID 11330046.
• Kadowaki T, Hara K, Kubota N, Tobe K, Terauchi Y, Yamauchi T, et al. (2002). "The role of PPARgamma in high-fat diet-induced obesity and insulin resistance". Journal of Diabetes and Its Complications. 16 (1): 41–5. doi:10.1016/S1056-8727(01)00206-9. PMID 11872365.
• Wakino S, Law RE, Hsueh WA (2002). "Vascular protective effects by activation of nuclear receptor PPARgamma". Journal of Diabetes and Its Complications. 16 (1): 46–9. doi:10.1016/S1056-8727(01)00197-0. PMID 11872366.
• Takano H, Komuro I (2002). "Roles of peroxisome proliferator-activated receptor gamma in cardiovascular disease". Journal of Diabetes and Its Complications. 16 (1): 108–14. doi:10.1016/S1056-8727(01)00203-3. PMID 11872377.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.