Disease relevance of PPARG

• Rare alleles of PPARG are associated significantly with Crohn's disease in humans [1].
• The germline transmission of a transactivation-deficient mutation in PPARG suggests that autosomal dominant partial lipodystrophy is genetically heterogeneous [2].
• PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy [2].
• Delineation, functional validation, and bioinformatic evaluation of gene expression in thyroid follicular carcinomas with the PAX8-PPARG translocation [3].
• PPARD and PPARG haplotypes are independent determinants of plasma levels of lipids, severity of coronary atherosclerosis and its response to therapy [4].
• We identified a PPARG mutation, C190S, causing partial lipodystrophy with metabolic alterations in three affected family members [5].
• PPARgamma is expressed in all vascular cells, where its activators exhibit anti-inflammatory and anti-atherogenic properties, suggesting that PPARgamma ligands could influence important processes in all phases of atherogenesis [6].
• Whether the increased expression of the PPARgamma1 receptor may be beneficial or not for a PPARgamma ligand-based treatment of atopic dermatitis, is currently under investigation [7].
• PPARgamma overexpression decreased multiple myeloma cell proliferation and induced spontaneous apoptosis even in the absence of exogenous ligand [8].

Psychiatry related information on PPARG

• Recent data indicate that PPARgamma (peroxisome proliferator-activated receptor gamma) could be involved in the modulation of the amyloid cascade causing Alzheimer's disease [9].
• Does peroxisome proliferator-activated receptor gamma genotype (Pro12ala) modify the association of physical activity and dietary fat with fasting insulin level [10]?
• This is the first study to suggest that a genetic interaction involving ADRB3 and PPARG variants influences eating behavior in children [11].

High impact information on PPARG

• The nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma) is a transcription factor that is activated by polyunsaturated fatty acids and their metabolites and is essential for fat cell formation [12].
• Although obesity is a strong risk factor for type 2 diabetes mellitus and other metabolic diseases, potent PPAR gamma activators such as the glitazone drugs lower glucose and lipid levels in patients with type 2 diabetes and also have antiatherosclerotic and antihypertensive effects [12].
• The unusual ligand-binding properties of PPAR gamma suggest that it will be possible to discover new chemical classes of receptor "modulators" with distinct pharmacological activities for the treatment of type 2 diabetes and other metabolic diseases [12].
• Identification of these molecules has yielded clues to the biochemical pathways that ultimately result in transcriptional activation via PPAR-gamma and C/EBP [13].
• In an era marked by the increasing prevalence of obesity, diabetes, and cardiovascular disease, the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) has emerged as a transcriptional regulator of metabolism whose activity can be modulated by direct binding of small molecules [14].

Chemical compound and disease context of PPARG

• Moreover, primary human liposarcoma cells can be induced to undergo terminal differentiation by treatment with the PPAR gamma ligand pioglitazone, suggesting that the differentiation block in these cells can be overcome by maximal activation of the PPAR pathway [15].
• Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor [15].
• In this study, we have examined the effects of the PPAR gamma ligand ciglitazone and the RXR ligand SR11237 on growth and induction of retinoic acid receptor (RAR) beta expression in breast and lung cancer cells [16].
• Troglitazone (TGZ) is a peroxisome proliferator-activated receptor gamma (PPAR gamma) ligand that has pro-apoptotic activity in human colon cancer [17].
• Transforming growth factor-beta (TGF-beta) activates cytosolic phospholipase A2alpha (cPLA2alpha)-mediated prostaglandin E2 (PGE)2/EP1 and peroxisome proliferator-activated receptor-gamma (PPAR-gamma)/Smad signaling pathways in human liver cancer cells. A novel mechanism for subversion of TGF-beta-induced mitoinhibition [18].

Biological context of PPARG

• The variant PPARG genotype was associated with a reduced recurrence risk (HR, 0.41; 95% CI, 0.20 to 0.86) among untreated patients [19].
• Our findings are consistent with the idea that mutant PPARG can underlie the partial lipodystrophy phenotype [2].
• Association of the Pro12Ala and C1431T variants of PPARG and their haplotypes with susceptibility to Type 2 diabetes [20].
• METHODS: We determined the PPARG genotype of a large Scottish cohort of Type 2 diabetic patients ( n=1997) and compared allele frequencies with a cohort of local children ( n=2444) and a middle-aged, population-based cohort from Scotland ( n=1061) [20].
• High levels of expression of PPARG and the gene encoding its interacting protein, PPARGC1A, in most EMCs suggest activation of lipid metabolism pathways in this tumour [21].

Anatomical context of PPARG

• Modulation of cytokine-induced cyclooxygenase 2 expression by PPARG ligands through NFkappaB signal disruption in human WISH and amnion cells [22].
• To test this hypothesis in a broader range of cancers we examined a series of carcinomas of the cervix, endometrium, ovary, prostate, and kidney for germline sequence variation in PPARG [23].
• A genetic polymorphism (C161T) at exon 6 of PPAR gamma gene (PPARG) was reported to be associated with the onset of coronary artery disease [24].
• Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells [25].
• Of note, a highly significant inverse correlation between adipocyte PPAR-gamma expression and BMI (r = -0.7, P = 0.0005) was found [26].

Associations of PPARG with chemical compounds

• Candidate gene sequencing showed that all four affected subjects were heterozygous for a novel T-->A mutation at PPARG nucleotide 1164 in exon 5 that predicted substitution of phenylalanine at codon 388 by leucine (F388L) [2].
• Analysis of the coding region of PPARG revealed C to T heterozygous mutation at nucleotide 1273 in exon 6 which changes a highly conserved residue, arginine at position 425 to cysteine (R425C) in the patient FX200.21 [27].
• Plasma triglyceride levels (P = 0.044), the mean number of coronary lesions (P = 0.026) and changes in minimum lumen diameter in response to fluvastatin (P = 0.022) were also associated with PPARG haplotypes [4].
• Using primary amnion and WISH cells, we evaluated the effects of pharmacological (thiazolidinediones) and putative endogenous (15-deoxy-Delta(12,14)-prostaglandin J2, 15d-PGJ2) PPARG ligands on cytokine-induced NFkappaB activation, COX2 expression, and PGE2 production [22].
• A single amino acid, which is tyrosine in PPAR alpha and histidine in PPAR gamma, imparts subtype selectivity for both thiazolidinedione and nonthiazolidinedione ligands [28].
• Our data indicate that the reduced transcriptional activity of PPARgamma R425C is not caused by impaired corepressor release, but due to reduced dimerization with retinoic acid X receptor alpha in combination with reduced ligand binding and subsequent coactivator binding [29].
• Both 15-d-PGJ2 and troglitazone blocked C/EBPbeta transcriptional activity by forming PPARgamma complexes with C/EBPbeta [30].
• Neither PPARG P12A nor five other variants significantly affected the impact of troglitazone on insulin sensitivity in 340 participants at 1 yr [31].
• Insulin alone stimulated expression of PPAR-gamma, alpha-subunit and beta-subunit of insulin receptor, and IRS-1 up to 174% (P < 0.001), 692% (P < 0.014), 275% (P < 0.024), and 431% (P < 0.01), respectively [32].
• Mutations within the context of the full-length PGC-1alpha indicate that the first PGC-1alpha motif is necessary and sufficient for PGC-1alpha to coactivate PPARgamma in the presence or absence of rosiglitazone [33].

Physical interactions of PPARG

• All PPARs are, albeit to different extents, activated by fatty acids and derivatives; PPAR-alpha binds the hypolipidemic fibrates whereas antidiabetic glitazones are ligands for PPAR-gamma [34].
• Our data highlight a new PPAR-gamma-dependent inhibitory mechanism on IL-1beta-mediated cartilage degradation occurring through DNA binding competition on the composite PPRE/AP1 site in the MMP1 promoter [35].
• PPRE-2, at +48 bases relative to the transcription start site, is required for the induction of SSAT by sulindac sulfone and is specifically bound by PPAR gamma in the Caco-2 cells as shown by transfection and gel shift experiments [36].
• RESULTS: We have used this system to determine the binding affinities of human estrogen receptor beta ligand binding domain (ERbeta LBD) and human peroxisome proliferator activated receptor gamma ligand binding domain (PPARgamma LBD) to a set of 34 coactivator peptides [37].
• Furthermore, PPAR gamma physically interacts with Smad3 but not Smad4 in vitro in glutathione S-transferase pull-down experiments [38].

Regulatory relationships of PPARG

• Higher concentrations increased VEGF levels and stimulated angiogenesis by activating PPAR-gamma [39].
• PPARalpha (NR1C1) controls lipid oxidation and clearance in hepatocytes and PPARgamma (NR1C3) promotes preadipocyte differentiation and lipogenesis [40].
• Cyclooxygenase-2 is induced in monocytes by peroxisome proliferator activated receptor gamma and oxidized alkyl phospholipids from oxidized low density lipoprotein [41].
• Our results show that Egr-1 is induced dramatically by TGZ but not by other PPAR gamma ligands [17].
• PPAR-gamma ligands stimulated IL-6 secretion and induced enhancement of IL-6 mRNA levels [42].
• Lentiviral short hairpin RNA-mediated knockdown of DSCR1 blocks PPARgamma inhibition of proliferation and invasion, indicating that DSCR1 is required for suppression of transformed properties of early stage colorectal cancer cells by PPARgamma [43].
• The electrophoretic mobility shift and chromatin immunoprecipitation (ChIP) assays evidenced a functional interaction between PPARgamma and Sp1 in regulating p21Cip1/WAF1 [44].
• Cytokine release correlated with nuclear PPARgamma localization; CSE reduced the amount of activated PPARgamma located in the nucleus and formed aldehyde adducts as PPARgamma protein carbonyls [45].

Other interactions of PPARG

• Inhibition of AP-1 activation and COX-2 or VEGF transcriptional induction by this cyclopentenone was found to be independent of peroxisome proliferator-activated receptor-gamma (PPARgamma) because it was not affected by either expression of a dominant negative form of PPARgamma or the use of a PPARgamma antagonist [46].
• Association of common polymorphisms in inflammatory genes interleukin (IL)6, IL8, tumor necrosis factor alpha, NFKB1, and peroxisome proliferator-activated receptor gamma with colorectal cancer [47].
• Regulation of retinoic acid receptor beta expression by peroxisome proliferator-activated receptor gamma ligands in cancer cells [16].
• Low Rtz concentrations (close to K(d) values for PPAR-gamma, 0.1 to 1 microm) inhibited the effects of IL-1beta on (35)S-sulfated proteoglycan production and gelatinolytic activities and downregulated MMP1 expression at mRNA and protein levels [35].
• Our results suggest that Egr-1 induction is a unique property of TGZ compared with other PPAR gamma ligands and is independent of PPAR gamma activation [17].
• PPARgamma may mediate IFN-gamma-stimulated collagen transcription down-regulation and MHC II up-regulation by interacting with CIITA as well as regulating CIITA expression [48].

Analytical, diagnostic and therapeutic context of PPARG

• The separate and combined effects of the PPARG Pro(12)Ala polymorphism and the KCNJ11 Glu(23)Lys polymorphisms on risk of type 2 diabetes were investigated in relatively large-scale, case-control studies [49].
• METHODS AND RESULTS: We performed a cohort study of 2016 individuals and used Cox proportional hazards to analyze risk of myocardial infarction or death by PPARG Pro12Ala and C1431T genotypes, adjusting for age, sex, and smoking status [50].
• Gel shift analysis indicated that PPAR gamma, in the presence of RXR, formed a strong complex with a retinoic acid response element (beta retinoic acid response element) in the RAR beta promoter [16].
• Immunocytochemistry, electrophoretic mobility shift, and transient transfection assays revealed a functional PPAR-gamma in chondrocytes in vitro [35].
• Expression of adipogenic transcription factors, peroxisome proliferator-activated receptor gamma co-activator 1, IL-6 and CD45 in subcutaneous adipose tissue in lipodystrophy associated with highly active antiretroviral therapy [51].

References