Disease relevance of PPARGC1A

• Increased risk of obesity associated with the variant allele of the PPARGC1A Gly482Ser polymorphism in physically inactive elderly men [1].
• In this study, we examined whether the PPARGC1A gene locus is associated with type 2 diabetes mellitus [2].
• CONCLUSIONS/INTERPRETATION: Our findings confirm that sex and age should be considered when investigating the influence of the PPARGC1A Gly482Ser polymorphism on metabolic disease [1].
• We therefore ascertained associations of PPARGC1A polymorphisms with asymptomatic carotid atherosclerosis [3].
• The genotype-combination analysis of the associated PPARGC1A Thr612Met variant and the associated PPARGC1B Ala203Pro variant suggests an allele dose-dependent breast cancer risk (P(trend) = 0.0004) [4].

Psychiatry related information on PPARGC1A

• Whenever possible, the level of physical activity should be addressed in future studies on disease risk associated with PPARGC1A Gly482Ser [1].

High impact information on PPARGC1A

• Suppression of Reactive Oxygen Species and Neurodegeneration by the PGC-1 Transcriptional Coactivators [5].
• Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1 [6].
• Recent studies have elucidated the function of the PGC-1 coactivators in different tissues and have highlighted the implications of PGC-1 dysregulation in diseases such as diabetes, obesity, cardiomyopathy, or neurodegeneration [7].
• One of the best-studied examples of coactivator control of metabolic pathways is the peroxisome proliferator-activated receptor coactivator 1 (PGC-1) family [7].
• Once PGC-1 alpha is activated, it powerfully induces and coordinates gene expression that stimulates mitochondrial oxidative metabolism in brown fat, fiber-type switching in skeletal muscle, and multiple aspects of the fasted response in liver [8].

Chemical compound and disease context of PPARGC1A

• These data suggest that increased PGC-1 expression and subsequent hepatic glucose production contribute to the insulin resistance observed in the IUGR juvenile rat [9].
• CONCLUSION: These findings suggest that PGC-1 can play a role in the prevention of cholesterol gallstone disease in humans; this might take place via interaction with the bile acid receptor FXR, whose protective role in cholelithiasis has been suggested by recent evidence in animal models and other coactivators [10].

Biological context of PPARGC1A

• RESULTS: There was no strong association between SNPs or haplotypes of PPARGC1A and type 2 diabetes [2].
• Therefore, we investigated the effects of single nucleotide polymorphisms in PPARGC1A on body composition and glucose tolerance and on insulin sensitivity and secretion [11].
• CONCLUSIONS/INTERPRETATION: The observation that PPARGC1A and the PPARs were upregulated in the adipose tissue of type 2 diabetic patients, along with the finding that adipose tissue from some patients with type 2 diabetes can express UCP1 mRNA, suggests that in these patients white adipose tissue may move towards a brown adipose tissue phenotype [12].
• Therefore, genetic variation of PPARGC1A could be implicated in the onset of type 2 diabetes [2].
• RESULTS: Two haplotype blocks in PPARGC1A were observed, one in the promoter region (G-1774A, A-1679G, T-1422C, A-1278G, C-543A) and one in the coding region and 3' regions (Thr394Thr, Asp475Asp, Gly482Ser, Thr528Thr, Thr612Met, G+2381A) [11].

Anatomical context of PPARGC1A

• AIMS/HYPOTHESIS: The variant allele of the Gly482Ser polymorphism in peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PPARGC1A or PGC1alpha), a critical determinant of skeletal muscle metabolism, has been associated with obesity and type 2 diabetes [1].
• Associations of PPARGC1A haplotypes with plaque score but not with intima-media thickness of carotid arteries in middle-aged subjects [3].
• AIMS/HYPOTHESIS: Peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1 (PPARGC1), a coactivator regulating the transcription of genes involved in oxidative metabolism, is downregulated in patients with type 2 diabetes and in their first-degree relatives [13].
• To identify other, perhaps more precise mechanisms contributing to PPAR subtype specificity, we studied PGC-1 recruitment by PPARs using a previously described hormone response element in the human UCP1 promoter and a human brown adipocyte cell line as our model system [14].
• The peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1 (PGC-1) can induce mitochondria biogenesis and has been implicated in the development of oxidative type I muscle fibers [15].

Associations of PPARGC1A with chemical compounds

• Haplotypes of PPARGC1A are associated with glucose tolerance, body mass index and insulin sensitivity in offspring of patients with type 2 diabetes [11].
• Finally, PERC enhances the ERalpha-mediated response to the partial agonist tamoxifen, while PGC-1 modestly represses it [16].
• Both the N-terminal region, with the LXXLL motif, and the C-terminal region, with a serine/arginine-rich domain (RS domain), in PGC-1 alpha were required for full activation of CAR [17].
• A single nucleotide polymorphism within the coding region of the PGC-1 gene predicts a glycine to serine substitution at amino acid 482 and has been associated with type 2 diabetes in a Danish population [18].
• As in rodents, PGC-1 is involved in the transcriptional regulation of the UCP1 gene in humans and mediates the effects of PPARalpha and PPARgamma agonists and retinoic acid [14].
• We have shown for the first time that PPARGC1A might be important in human islet insulin secretion and that expression of PPARGC1A in human islets can be regulated by both genetic and epigenetic factors [19].

Physical interactions of PPARGC1A

• Second, PGC-1 interacts physically with ERRalpha and enables it to activate transcription [20].

Regulatory relationships of PPARGC1A

• First, PGC-1 induces the expression of ERRalpha [20].
• These results indicate that signaling via PKB to FKHR can partly account for the effect of insulin to regulate the PGC-1 promoter activity via the IRSs [21].
• These data support a model whereby PPAR subtype specificity is regulated by recruitment of PGC-1 [14].
• We have shown that this sequence is fundamental for fatty acids or PGC1-induced transcriptional activation of the CPT1A gene [22].
• We also provide evidence that interaction of the repressor with PGC-1 is regulated by mitogen-activated protein kinase (MAPK) signaling [23].

Other interactions of PPARGC1A

• PERC and PGC-1 are likely to have different functions in ER signaling [16].
• 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 [24].
• Furthermore, the adipose tissue expression of PGC-1 and IRS-1 correlated with insulin action in vivo [25].
• In contrast, no differential expression of PGC-1, GLUT-4, or IRS-1 was found in the skeletal muscle of insulin-resistant vs insulin-sensitive subjects [25].
• PGC-1 and PPAR-alpha mRNA expression increased by 2.7- and 2.2-fold (P < 0.01), respectively, after endurance training [15].

Analytical, diagnostic and therapeutic context of PPARGC1A

• PPARGC1A/B mRNA was quantified by RT-PCR [26].
• CONCLUSIONS/INTERPRETATION: This meta-analysis of data from the current and published studies supports a modest role for the Gly482Ser PPARGC1A variant in type 2 diabetes risk [27].
• CONCLUSIONS/INTERPRETATION: Enhanced insulin-stimulated glycogen synthesis in human skeletal muscle cell culture coincides with increased GLUT4 and PGC1 mRNA expression following treatment with various antidiabetic agents [28].
• An immunoprecipitation assay reveals that PGC-1 and RXRalpha interact in vivo [29].
• We demonstrate further, in a mammalian two-hybrid assay, that this physical interaction also requires the presence of the AF-2 region of RXR to interact with the LXXLL motif of PGC-1, which is consistent with our protein-protein interaction results [29].

References