Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferator-activated receptors (PPAR) exist in three different forms, alpha (alpha), beta/delta (beta/delta), or gamma (gamma), all of which are expressed in skeletal muscle and play a critical role in the regulation of oxidative metabolism. The purpose of this investigation was to determine the mRNA expression pattern of the different PPARs and peroxisome proliferator-activated receptor alpha coactivator-1 alpha (PGC-1alpha) in muscles that largely rely on either glycolytic (plantaris) or oxidative (soleus) metabolism. Further, we also examined the alterations in the PPARs mRNA expression after one bout of endurance exercise or after 12 weeks of exercise training in the different muscles. Female Sprague-Dawley rats (5-8 months) were either run on the treadmill once or exercised trained for 12 weeks. The muscles were removed 24 h after the last bout of exercise. The results demonstrated with the exception of PPAR beta/delta, the PPAR mRNAs are expressed to a greater extent in the soleus muscle than in the plantaris muscle in sedentary animals. PPARgamma was the least abundantly expressed PPAR in either the soleus or the plantaris muscle. With respect to exercise training, only PPARgamma mRNA expression increased in the soleus muscle, while PPARbeta/delta and gamma mRNA levels increased in the plantaris muscle. Minimal changes were detected in any of the PPARs with one bout of exercise training. These results suggest that PPARgamma mRNA levels are the lowest in skeletal muscle among all of the PPARs and PPARgamma mRNA is the most responsive to changes in physical activity levels.
Mol Cell Biochem 2009 Dec
PMID:Alterations in peroxisome proliferator-activated receptor mRNA expression in skeletal muscle after acute and repeated bouts of exercise. 1958 29

Peroxisome proliferator-activated receptor delta (PPARdelta) is an essential determinant of basal myocardial fatty acid oxidation (FAO) and bioenergetics. We wished to determine whether increased lipid loading affects the PPARdelta deficient heart in transcriptional regulation of FAO and in the development of cardiac pathology. Cardiomyocyte-restricted PPARdelta knockout (CR-PPARdelta(-/-)) and control (alpha-MyHC-Cre) mice were subjected to 48 h of fasting and to a long-term maintenance on a (28 weeks) high-fat diet (HFD). The expression of key FAO proteins in heart was examined. Serum lipid profiles, cardiac pathology, and changes of various transduction signaling pathways were also examined. Mice subjected to fasting exhibited upregulated transcript expression of FAO genes in the CR-PPARdelta(-/-) hearts. Moreover, long-term HFD in CR-PPARdelta(-/-) mice induced a strikingly greater transcriptional response. After HFD, genes encoding key FAO enzymes were expressed remarkably more in CR-PPARdelta(-/-) hearts than in those of control mice. Despite the marked rise of FAO gene expression, corresponding protein expression remained low in the CR-PPARdelta(-/-) heart, accompanied by abnormalities in sarcomere structures and mitochondria that were similar to those of CR-PPARdelta(-/-) hearts with regular chow feeding. The CR-PPARdelta(-/-) mice displayed increased expression of PPARgamma co-activator-1alpha (PGC-1alpha) and PPARalpha in the heart with deactivated Akt and p42/44 MAPK signaling in response to HFD. We conclude that PPARdelta is an essential determinant of myocardial FAO. Increased lipid intake activates cardiac expression of FAO genes via PPARalpha/PGC-1alpha pathway, albeit it is not sufficient to improve cardiac pathology due to PPARdelta deficiency.
J Mol Cell Cardiol 2009 Oct
PMID:High-fat feeding in cardiomyocyte-restricted PPARdelta knockout mice leads to cardiac overexpression of lipid metabolic genes but fails to rescue cardiac phenotypes. 1959 95

Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is capable of coactivating several nuclear receptors and transcription factors that participate in the regulation of multiple metabolic processes, including gluconeogenesis, mitochondrial biogenesis, and adaptive thermogenesis. Uridine phosphorylase (UPase) catalyzes the reversible conversion of uridine into uracil and contributes to the antineoplastic activity of 5'-deoxy-5-fluorouridine (5'-DFUR) and homeostasis of uridine levels in plasma and tissues. This study demonstrates uridine phosphorylase as a novel target gene of PGC-1alpha, which induces the transcription and enzymatic activity of UPase in various cancer cells and thus augments their susceptibility to 5'-DFUR. PGC-1alpha-induced activation of UPase expression occurs at its transcription level that is mediated by an estrogen-related receptor (ERR) binding site (-1078 to -1070 base pairs) mapped in the promoter region of UPase gene. Our mutational studies using luciferase reporter construct together with electrophoretic mobility shift assays confirm the binding of ERR to PGC-1alpha-responsive element. Moreover, the inhibition of PGC-1alpha/ERRalpha-dependent signaling by 3-[4-(2,4-bis-trifluoromethylbenzyloxy)-3-methoxyphenyl]-2-cyano-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)acrylamide (XCT790) compromises the ability of PGC-1alpha to induce the transcript of UPase, indicating PGC-1alpha-dependent and ERRalpha-mediated up-regulation of UPase. Finally, the overexpression of PGC-1alpha sensitizes breast and colon cancer cells to growth inhibition by 5'-DFUR presumably by inducing apoptosis in tumor cells and XCT790 can inhibit the process. Taken together, our results corroborate the regulatory function of PGC-1alpha in uridine homeostasis and imply its links with the energy metabolism. The mechanistic elucidation of this association between both cellular pathways should advance the clinical use of 5-fluorouracil-based chemotherapy.
Mol Pharmacol 2009 Oct
PMID:Peroxisome proliferator-activated receptor gamma coactivator-1alpha enhances antiproliferative activity of 5'-deoxy-5-fluorouridine in cancer cells through induction of uridine phosphorylase. 1960 72

Burn injuries to extensive areas of the body are complicated by muscle catabolism. Elucidating the molecular mechanisms that mediate this catabolism may facilitate the development of a medical intervention. Here, we assessed the functional classification of genes that were differentially expressed in skeletal muscle following burn injury in 19 children (5.2+/-4.0 years of age), (64+/-15% total burn surface area, TBSA) relative to 13 healthy controls (11.9+/-6.0 years of age). Microarray analysis of samples taken within 10 days of burn injury revealed altered expression of a variety of genes, including some involved in cell and organelle organization and biogenesis, stress response, wound response, external stimulus response, regulation of apoptosis and intracellular signaling. The genes that encode peroxisome proliferator-activated receptors (PPARs; 3 isotypes PPARalpha, PPARgamma and PPARdelta also known as PPARbeta or PPARbeta/delta), which may serve as transcriptional nodal points and therapeutic targets for metabolic syndromes, were among those affected. In particular, expression of the main mitochondrial biogenesis factor PPARgamma-1beta (or PGC-1beta) was downregulated (P<0.0001), while the expression of PPARdelta was upregulated (P<0.001). Expression of PGC-1alpha, the closest homolog of PGC-1beta was upregulated (P=0.0037), and expression of the gene encoding mitochodrial uncoupling protein 2 (UCP2) was also upregulated (P=0.008). These results suggest that altered PPAR and mitochondrial gene expression soon after burn injury may lead to metabolic and mitochondrial dysfunction in human skeletal muscle.
Int J Mol Med 2009 Sep
PMID:Microarray analysis suggests that burn injury results in mitochondrial dysfunction in human skeletal muscle. 1963 32

Mitochondrial biogenesis is inherent to adipocyte differentiation. Mitochondrial dysfunction leads to abnormal lipid accumulation or the deterioration of the differentiation process. The aim of this study is to investigate the mitochondrial development during the differentiation of rat primary adipocytes and the effect of mitochondrial dysfunction on this process. We found, for the first time, that the number of mitochondria markedly increased during adipocyte differentiation by transmission electron microscopy. By immunofluorescence staining that the protein content of Cyt c increased in differentiated adipocyte in comparison with preadipocyte. The mRNA expression levels of mitochondrial gene including cytochromes c (Cyt c), malate dehydrogenases (MDH), and peroxisome proliferator activated receptor (PPAR) gamma coactivator-1beta (PGC-1beta) significantly increased along with the proceeding of adipocyte differentiation. The damage to mitochondrial respiratory chain function by rotenone caused significant decrease in gene expressions including mitochondrial MDH and PGC-1beta, and PPARgamma, CAAT/enhancer binding protein alpha (C/EBPalpha) and sterol regulatory element binding protein-1c (SREBP-1c), which are known as transcription factors of differentiation, and differentiation marker gene named fatty acid synthetase. Moreover, an apparent decrease was found in the synthesis of triglyceride and ATP due to the damage to mitochondria by rotenone. Based on the above results, our present study revealed that the density and oxidative capacity of mitochondrial markedly increased during primary adipocyte differentiation, and on the other hand, we suggested that mitochondria dysfunction might inhibit the differentiation process.
Mol Biol Rep 2010 Jun
PMID:Mitochondrial development and the influence of its dysfunction during rat adipocyte differentiation. 1969 1

Although both inflammatory and metabolic complications occur during sepsis and endotoxemia, relatively few studies have examined the molecular mechanism underlying LPS-modulated metabolic changes during sepsis. In this report, we have demonstrated that LPS suppresses free fatty acid (FFA) oxidation, and consequently contributes to elevated plasma levels of FFA and triglyceride (TG). Furthermore, this process depends upon the interleukin-1 receptor associated kinase 1 (IRAK-1), one of the key TLR4 intracellular signaling kinases. IRAK-1(-/-) mice fail to exhibit the dramatic rise in plasma FFA and TG levels compared to wild-type (WT) mice following lethal LPS injection. Mechanistically, we demonstrated that LPS suppresses FFA oxidation through decreasing the expression levels of key FFA oxidative genes including CPT-1 and MCAD in both liver and kidney tissues of WT but not IRAK-1(-/-) mice. The expression of CPT-1 and MCAD is controlled by nuclear receptors and co-receptors including PPARalpha and PGC-1alpha. We observed that LPS selectively suppresses the levels of PPARalpha and PGC-1alpha in tissues from WT, but not IRAK-1(-/-) mice. Consequently, IRAK-1(-/-) mice have a higher survival rate following a lethal dose of LPS. Our current study reveals a novel role for IRAK-1 in the metabolic alterations induced by LPS.
Mol Immunol 2009 Dec
PMID:Molecular mechanism underlying the suppression of lipid oxidation during endotoxemia. 1977 84

PGC-1alpha is an inducible nuclear receptor coactivator with direct functions in both p300-mediated chromatin remodeling and Mediator-dependent transcription in vitro. Here, we have employed the PPARgamma- and TRalpha-activated brown adipose tissue-specific UCP-1 enhancer to investigate mechanistic aspects of PGC-1alpha function. We first demonstrate a cellular role for the PGC-1alpha-interacting MED1 subunit of Mediator in UCP-1 induction, as well as the accumulation of TRalpha, PPARgamma, PGC-1alpha, and MED1 on the UCP-1 enhancer in brown adipocytes. We then use biochemical assays to show that (i) PGC-1alpha is recruited to the TRalpha-RXRalpha-UCP-1 enhancer complex through interaction of an N-terminal LXXLL domain with TRalpha, (ii) MED1/Mediator displaces PGC-1alpha from TRalpha through LXXLL domain competition, and (iii) upon loss of PGC-1alpha-TRalpha interactions, PGC-1alpha remains associated with the enhancer complex through an interaction between PGC-1alpha and MED1 C-terminal domains. These results indicate dynamic MED1-dependent PGC-1alpha interactions related to functions in both chromatin remodeling and the transition to subsequent transcription initiation.
Mol Cell 2009 Sep 24
PMID:Dynamic interactions and cooperative functions of PGC-1alpha and MED1 in TRalpha-mediated activation of the brown-fat-specific UCP-1 gene. 1978 26

Estrogen shows a vasoprotective role through inhibiting the proliferation and migration of vascular smooth muscle cells (VSMCs). The mechanism underlying the effect of estrogen, however, is not completely understood. Here, we explored the role of peroxisome proliferator-activated receptor-gamma (PPARgamma) coactivator-1alpha (PGC-1alpha) in estrogen-mediated vasoprotection. Firstly, we showed that oleic acid (OA) decreased PGC-1alpha expression while stimulating VSMC proliferation and migration. In contrast, administration of VSMCs with 17beta-estradiol (E(2), 1 or 10nM) significantly restored OA-decreased PGC-1alpha expression, treatment with 10nM E(2) almost completely abolished OA-induced VSMC proliferation and migration. Secondly, by using PGC-1alpha siRNA, the inhibitory effect of E(2) on VSMC growth is strongly reduced via suppressing PGC-1alpha expression, indicating that E(2) may exert its role through restoring PGC-1alpha. Finally, E(2) (10nM) treatment inhibits OA-induced extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, however, suppression of PGC-1alpha expression abolishes this inhibitory effect of E(2). Our findings demonstrate for the first time that in OA-stimulated rat VSMCs, treatment with E(2) (1 or 10nM) diminishes VSMC proliferation and migration via restoring OA-decreased PGC-1alpha expression. This observation offers a novel molecular basis of the vasoprotective effect of estrogen.
Mol Cell Endocrinol 2010 Feb 05
PMID:17beta-estradiol inhibits oleic acid-induced rat VSMC proliferation and migration by restoring PGC-1alpha expression. 1978 68

Pathways involved in mitochondrial biogenesis associated with myogenic differentiation are poorly defined. Therefore, C(2)C(12) myoblasts were differentiated into multi-nucleated myotubes and parameters/regulators of mitochondrial biogenesis were investigated. Mitochondrial respiration, citrate synthase- and beta-hydroxyacyl-CoA dehydrogenase activity as well as protein content of complexes I, II, III and V of the mitochondrial respiratory chain increased 4-8-fold during differentiation. Additionally, an increase in the ratio of myosin heavy chain (MyHC) slow vs MyHC fast protein content was observed. PPAR transcriptional activity and transcript levels of PPAR-alpha, the PPAR co-activator PGC-1alpha, mitochondrial transcription factor A and nuclear respiratory factor 1 increased during differentiation while expression levels of PPAR-gamma decreased. In conclusion, expression and activity levels of genes known for their regulatory role in skeletal muscle oxidative capabilities parallel the increase in oxidative parameters during the myogenic program. In particular, PGC-1alpha and PPAR-alpha may be involved in the regulation of mitochondrial biogenesis during myogenesis.
Mol Cell Endocrinol 2010 Feb 05
PMID:Regulation of mitochondrial biogenesis during myogenesis. 1980 13

There are currently few successful therapies for castration-resistant prostate cancer (CRPC). CRPC is thought to result from augmented activation of the androgen/androgen receptor (AR) signaling pathway, which could be enhanced by AR cofactors. In this study, peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) was found to be an AR cofactor. PGC-1alpha interacted with the N-terminal domain of AR, was involved in the N- and C-terminal interaction of AR, and enhanced the DNA-binding ability of AR to androgen-responsive elements in the prostate-specific antigen enhancer and promoter regions to increase the transcription of AR target genes. Silencing of PGC-1alpha suppressed cell growth of AR-expressing prostate cancer (PCa) cells by inducing cell-cycle arrest at the G(1) phase, similar to inhibition of androgen/AR signaling. Furthermore, PGC-1alpha knock-down also suppressed cell growth in the castration-resistant LNCaP-derivatives. These findings indicate that PGC-1alpha is involved in the proliferation of AR-expressing PCa cells by acting as an AR coactivator. Modulation of PGC-1alpha expression or function may offer a useful strategy for developing novel therapeutics for PCa, including CRPC, which depends on AR signaling by overexpressing AR and its coactivators.
Mol Endocrinol 2010 Jan
PMID:Peroxisome proliferator-activated receptor gamma coactivator-1alpha interacts with the androgen receptor (AR) and promotes prostate cancer cell growth by activating the AR. 1988 83


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