Peroxisome proliferator-activated receptor gamma
Short name=PPAR-gamma
Alternative name(s):
Nuclear receptor subfamily 1 group C member 3
Gene names
Name: PPARG
Synonyms: NR1C3
Function
高脂血症治療薬、脂肪酸などペルオキシソーム増殖因子の核内受容体で、PPAR応答エレメントに結合し
Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses. Ref.1 Ref.23 Ref.25 Ref.27
Enzyme regulation
PDPK1 activates its transcriptional activity independently of its kinase activity. Ref.23
Subunit structure
Heterodimer with other nuclear receptors, such as RXRA. The heterodimer with the retinoic acid receptor RXRA is called adipocyte-specific transcription factor ARF6. Interacts with NCOA6 coactivator, leading to a strong increase in transcription of target genes. Interacts with coactivator PPARBP, leading to a mild increase in transcription of target genes. Interacts with NOCA7 in a ligand-inducible manner. Interacts with NCOA1 and NCOA2 LXXLL motifs. Interacts with ASXL1, ASXL2, DNTTIP2, FAM120B, MAP2K1/MEK1, NR0B2, PDPK1, PRDM16, PRMT2 and TGFB1I1. Interacts (when activated by agonist) with PPP5C. Interacts with HELZ2 and THRAP3; the interaction stimulates the transcriptional activity of PPARG. Ref.16 Ref.18 Ref.19 Ref.20 Ref.21 Ref.22 Ref.23 Ref.24 Ref.26 Ref.27 Ref.29
Subcellular location
Nucleus. Cytoplasm. Note: Redistributed from the nucleus to the cytosol through a MAP2K1/MEK1-dependent manner. Ref.24 Ref.27
Tissue specificity
Highest expression in adipose tissue. Lower in skeletal muscle, spleen, heart and liver. Also detectable in placenta, lung and ovary. Ref.1
Post-translational modification
O-GlcNAcylation at Thr-84 reduces transcriptional activity in adipocytes By similarity.
Phosphorylated in basal conditions and dephosphorylated when treated with the ligand. May be dephosphorylated by PPP5C. The phosphorylated form may be inactive and dephosphorylation at Ser-112 induces adipogenic activity By similarity.
Polymorphism
Genetic variation in PPARG may influence body mass index (BMI) [MIM:606641]. BMI reflects the amount of fat, lean mass, and body build.
Genetic variations in PPARG influence the carotid intimal medial thickness (CIMT) [MIM:609338]. CIMT is a measure of atherosclerosis that is independently associated with traditional atherosclerotic cardiovascular disease risk factors and coronary atherosclerotic burden. 35 to 45% of the variability in multivariable-adjusted CIMT is explained by genetic factors.
Involvement in disease
Defects in PPARG can lead to type 2 insulin-resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer.
Obesity (OBESITY) [MIM:601665]: A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.
Note: Disease susceptibility may be associated with variations affecting the gene represented in this entry. Ref.42
Lipodystrophy, familial partial, 3 (FPLD3) [MIM:604367]: A form of lipodystrophy characterized by marked loss of subcutaneous fat from the extremities. Facial adipose tissue may be increased, decreased or normal. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.48 Ref.49
Glioma 1 (GLM1) [MIM:137800]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes.
Note: Disease susceptibility may be associated with variations affecting the gene represented in this entry. Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility.
Sequence similarities
Belongs to the nuclear hormone receptor family. NR1 subfamily.
Contains 1 nuclear receptor DNA-binding domain.
Regions
- DNA binding 136 – 210 75 Nuclear receptor
- Zinc finger 139 – 159 21 NR C4-type
- Zinc finger 176 – 198 23 NR C4-type
- Region 205 – 280 76 Interaction with FAM120B By similarity
- Region 317 – 505 189 Ligand-binding
Peroxisome proliferator-activated receptor alpha
Short name=PPAR-alpha
Alternative name(s):
Nuclear receptor subfamily 1 group C member 1
Gene names
Name: PPARA
Synonyms: NR1C1, PPAR
Function
Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety By similarity. Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the ACOX1 and P450 genes. Transactivation activity requires heterodimerization with RXRA and is antagonized by NR2C2. Ref.1 Ref.13 Ref.15 Ref.16
Subunit structure
Heterodimer; with RXRA. This heterodimerization is required for DNA binding and transactivation activity. Interacts with AKAP13, LPIN1 and PRDM16. Also interacts with PPARBP coactivator in vitro. Interacts with CITED2; the interaction stimulates its transcriptional activity By similarity. Interacts with NCOA3 and NCOA6 coactivators. Interacts with ASXL1 AND ASXL2. Ref.13 Ref.14 Ref.16 Ref.17 Ref.18 Ref.20
Subcellular location
Nucleus.
Tissue specificity
Skeletal muscle, liver, heart and kidney. Ref.2 Ref.3
Sequence similarities
Belongs to the nuclear hormone receptor family. NR1 subfamily.
Contains 1 nuclear receptor DNA-binding domain.
