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Peroxisome proliferator-activated receptor gamma

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PPARG
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPPARG, CIMT1, GLM1, NR1C3, PPARG1, PPARG2, PPARgamma, peroxisome proliferator activated receptor gamma, PPARG5
External IDsOMIM: 601487; MGI: 97747; HomoloGene: 7899; GeneCards: PPARG; OMA:PPARG - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5468

19016

Ensembl

ENSG00000132170

ENSMUSG00000000440

UniProt

P37231

P37238

RefSeq (mRNA)

NM_001127330
NM_011146
NM_001308352
NM_001308354

RefSeq (protein)

NP_001120802
NP_001295281
NP_001295283
NP_035276

Location (UCSC)Chr 3: 12.29 – 12.43 MbChr 6: 115.34 – 115.47 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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]

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:

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

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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