Disease relevance of Ppargc1a

• Here we show that PGC-1-deficient mice, generated by adenoviral delivery of PGC-1 RNA interference (RNAi) to the liver, experience fasting hypoglycemia [1].
• Mice lacking SHP show increased basal expression of PGC-1alpha, increased energy expenditure, and resistance to diet-induced obesity [2].
• Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1alpha [3].
• These data show that PGC-1alpha links nutritional status to heme biosynthesis and acute hepatic porphyria [3].
• Cardiac-specific overexpression of PGC-1 in transgenic mice resulted in uncontrolled mitochondrial proliferation in cardiac myocytes leading to loss of sarcomeric structure and a dilated cardiomyopathy [4].

Psychiatry related information on Ppargc1a

• Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1alpha in Huntington's disease neurodegeneration [5].
• PURPOSE: To explore whether a candidate polymorphism in the PGC-1alpha gene modifies the association between physical activity energy expenditure (PAEE) and predicted [OV0312]O2max ([OV0312]O2max.pred) [6].

High impact information on Ppargc1a

• Studies by and now show that resveratrol promotes longevity and improves glucose homeostasis in mice by stimulating the Sirt1-mediated deacetylation of the transcriptional coactivator PGC-1alpha [7].
• These studies suggest a key role for PGC-1alpha in the control of energy metabolism in the early stages of HD pathogenesis [8].
• We report here that mutant huntingtin causes disruption of mitochondrial function by inhibiting expression of PGC-1alpha, a transcriptional coactivator that regulates several metabolic processes, including mitochondrial biogenesis and respiration [8].
• Crossbreeding of PGC-1alpha knockout (KO) mice with HD knockin (KI) mice leads to increased neurodegeneration of striatal neurons and motor abnormalities in the HD mice [8].
• PPARgamma coactivator 1alpha (PGC-1alpha) is a potent stimulator of mitochondrial biogenesis and respiration [9].

Chemical compound and disease context of Ppargc1a

• Forced expression of PGC-1alpha in mouse and human hepatoma cells increases the mRNA of a subset of apolipoproteins implicated in very low density lipoprotein and triglyceride metabolism, including apolipoproteins A-IV, C-II, and C-III [10].
• Alterations of PPARalpha and its coactivator PGC-1 in cisplatin-induced acute renal failure [11].
• Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1alpha [12].

Biological context of Ppargc1a

• PGC-1 promotes cooperativity between cyclic AMP and glucocorticoid signalling pathways during hepatic gluconeogenesis [13].
• Overexpression of PGC-1 in CREB-deficient mice restored glucose homeostasis and rescued expression of gluconeogenic genes [13].
• Knockdown of hepatic TRB-3 expression improved glucose tolerance, whereas hepatic overexpression of TRB-3 reversed the insulin-sensitive phenotype of PGC-1-deficient mice [1].
• Together, our results suggest a transcriptional mechanism for chondrogenesis that is coordinated by PGC-1alpha [14].
• PGC-1alpha was also shown to activate ERRalpha gene expression [15].

Anatomical context of Ppargc1a

• The expression of Ppargc1a and Nrf1 was also stimulated by n-3 polyunsaturated fatty acids in 3T3-L1 cells [16].
• The nuclear hormone receptor coactivator PGC-1 (peroxisome proliferator-activated (PPAR)-gamma coactivator-1) has been implicated in the onset of type 2 diabetes [1].
• We conclude that ERRalpha serves as a critical nodal point in the regulatory circuitry downstream of PGC-1alpha to direct the transcription of genes involved in mitochondrial energy-producing pathways in cardiac and skeletal muscle [15].
• Regulation of the PGC-1alpha gene and that of mitochondrial 3-hydroxy-3-methyl-glutaryl-coenzyme A synthase, acyl-coenzyme A oxidase, and long-chain acyl-coenzyme dehydrogenase, marker genes of lipid catabolism, were dissociated in fetuses and neonates [17].
• The control of UCP1 is dissociated from that of PGC-1alpha or of mitochondriogenesis as revealed by a study using beta-less mouse brown adipocytes in culture [18].

Associations of Ppargc1a with chemical compounds

• Retroviral vector-mediated expression studies performed in 3T3-L1 cells demonstrated that PPARalpha and PGC-1 cooperatively induced the expression of PPARalpha target genes and increased cellular palmitate oxidation rates [19].
• Glutathione S-transferase "pulldown" studies revealed that in contrast to the previously reported ligand-independent interaction with PPARgamma, PGC-1 binds PPARalpha in a ligand-influenced manner [19].
• Only under the effects of starvation was PGC-1alpha gene expression induced in parallel to phosphoenolpyruvate carboxykinase and G6Pase mRNAs during the perinatal period [17].
• Importantly, introduction of ectopic PGC-1alpha can reverse the repression of most of these genes by epinephrine [20].
• This is due to the presence of a PPARgamma-responsive element in the distal region of the PGC-1alpha gene promoter that binds PPARgamma/retinoid X receptor heterodimers [21].
• These data link LRP130 and PGC-1alpha to defective hepatic energy homeostasis in LSFC, and reveal a novel regulatory mechanism of glucose homeostasis [22].

Physical interactions of Ppargc1a

• PGC-1alpha interacts with several nuclear receptors known to bind gluconeogenic promoters including the glucocorticoid receptor, hepatocyte nuclear factor 4alpha (HNF4alpha), and the peroxisome proliferator-activated receptors [23].
• Importantly, pRb was observed to bind the PGC-1alpha promoter and repress transcription [24].
• CONCLUSIONS: These results demonstrate that cisplatin deactivates PPARalpha by reducing its DNA binding activity and the availability of its tissue specific coactivator PGC-1 [11].
• Gel shift assays demonstrated that the PGC-1alpha-responsive element bound the estrogen-related receptor alpha (ERRalpha), a recently identified component of the PGC-1alpha signaling pathway [25].
• Using GST pull-down assays, PGC-1alpha directly interacted with in vitro-generated and nuclear Nurr1 [26].

Regulatory relationships of Ppargc1a

• Consistent with this finding, PGC-1alpha disruption in MSC by small interfering RNA inhibits Col2a1 expression during chondrogenesis [14].
• ERRalpha upregulated a subset of PGC-1alpha target genes involved in multiple energy production pathways, including cellular fatty acid transport, mitochondrial and peroxisomal fatty acid oxidation, and mitochondrial respiration [15].
• These findings suggest that contractile activity-induced activation of the p38 MAPK pathway promotes Pgc-1alpha gene expression and skeletal muscle adaptation [27].
• The orphan nuclear receptor SHP regulates PGC-1alpha expression and energy production in brown adipocytes [2].
• Therefore, p107 and pRb regulate PGC-1alpha expression to control the switch between white and brown adipocyte differentiation from a common pool of presumptive adult progenitors in fat tissue [24].

Other interactions of Ppargc1a

• Furthermore, overexpression of both PGC-1alpha and Sox9 induced expression of chondrogenic genes, including Col2a1, followed by chondrogenesis in the MSC and developing chick limb [14].
• Skeletal muscle-specific expression of a constitutively active activator of p38, MKK6E, in transgenic mice resulted in enhanced Pgc-1alpha and cytochrome oxidase IV protein expression in fast-twitch skeletal muscles [27].
• The independent regulation of PGC-1alpha and lipid catabolism genes was also found in peroxisome proliferator-activated receptor-alpha-null neonates, in which PGC-1alpha mRNA levels were unaffected whereas gene expression for 3-hydroxy-3-methyl-glutaryl-coenzyme A synthase and acyl-coenzyme A oxidase was impaired [17].
• Here, we examined the effect of aging on the skeletal muscle expression of two isoforms of the transcriptional peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1 (PGC-1) in an experimental murine model of accelerated aging, the senescence-accelerated mouse (SAM) [28].
• Dietary fat interacts with QTLs controlling induction of Pgc-1 alpha and Ucp1 during conversion of white to brown fat [29].

Analytical, diagnostic and therapeutic context of Ppargc1a

• Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-gamma coactivator 1alpha [20].
• Thus we related PGC-1alpha protein expression to cytochrome c oxidase (COX) activity in 1) tissues of varying oxidative capacities, 2) tissues from animals treated with T(3), and 3) skeletal muscle subject to contractile activity both in cell culture and in vivo [30].
• The expression levels of PGC-1alpha, mitochondrial proteins and GLUT4 were evaluated by Western blotting [31].
• These results illustrate the dissection of gene regulatory networks in a complex mammalian system, elucidate the mechanism of PGC-1alpha action in the OXPHOS pathway, and suggest that Erralpha agonists may ameliorate insulin-resistance in individuals with type 2 diabetes mellitus [32].
• Chromatin immunoprecipitation assays confirmed that PGC-1alpha and ERRalpha occupied the mPDK4 promoter in C(2)C(12) myotubes [25].

References