PPARdelta, but not PPARalpha, activates PGC-1alpha gene transcription in muscle.
ABSTRACT PGC-1alpha induces mitochondrial biogenesis in muscle and its activity has been related to insulin sensitization. Here, we report that fibrates induce PGC-1alpha gene expression in muscle both in vivo and in vitro. However, only activation via PPARdelta but not PPARalpha underlies this effect. PPARdelta induces PGC-1alpha gene transcription through a PPAR-response element in the PGC-1alpha promoter. Moreover, PGC-1alpha coactivates the PPARdelta-responsiveness of its own gene. A further positive autoregulatory loop of control relies on the induction of PPARdelta expression by PGC-1alpha. These data point to a distinct value of PPARdelta rather than PPARalpha agonists in the improvement of oxidative metabolism in muscle.
Article: TNF-alpha reduces PGC-1alpha expression through NF-kappaB and p38 MAPK leading to increased glucose oxidation in a human cardiac cell model.[show abstract] [hide abstract]
ABSTRACT: Inflammatory responses in the heart that are driven by sustained increases in cytokines have been associated with several pathological processes, including cardiac hypertrophy and heart failure. Emerging data suggest a link between cardiomyopathy and myocardial metabolism dysregulation. To further elucidate the relationship between a pro-inflammatory profile and cardiac metabolism dysregulation, a human cell line of cardiac origin, AC16, was treated with tumour necrosis factor-alpha (TNF-alpha). Exposure of AC16 cells to TNF-alpha inhibited the expression of peroxisome proliferator-activated receptor coactivator 1alpha (PGC-1alpha), an upstream regulator of lipid and glucose oxidative metabolism. Studies performed with cardiac-specific transgenic mice (Mus musculus) overexpressing TNF-alpha, which have been well characterized as a model of cytokine-induced cardiomyopathy, also displayed reduced PGC-1alpha expression in the heart compared with that of control mice. The mechanism by which TNF-alpha reduced PGC-1alpha expression in vitro appeared to be largely mediated via both p38 mitogen-activated protein kinase and nuclear factor-kappaB pathways. PGC-1alpha downregulation resulted in an increase in glucose oxidation rate, which involved a reduction in pyruvate dehydrogenase kinase 4 expression and depended on the DNA-binding activity of both peroxisome proliferator-activated receptor beta/delta and estrogen-related receptor alpha transcription factors. These results point to PGC-1alpha downregulation as a potential contributor to cardiac dysfunction and heart failure in metabolic disorders with an inflammatory background.Cardiovascular research 12/2008; 81(4):703-12. · 5.80 Impact Factor
Article: Peroxisome proliferator-activated receptor (PPAR) beta/delta: a new potential therapeutic target for the treatment of metabolic syndrome.[show abstract] [hide abstract]
ABSTRACT: Metabolic syndrome is defined as the clustering of multiple metabolic abnormalities, including abdominal obesity, dyslipidemia (high serum triglycerides and low serum HDL-cholesterol levels), glucose intolerance and hypertension. The pathophysiology underlying metabolic syndrome involves a complex interaction of crucial factors, but two of these, insulin resistance and obesity (especially visceral obesity), play a major role. The nuclear receptors Peroxisome Proliferator-Activated Receptors (PPAR)alpha and PPARgamma are therapeutic targets for hypertriglyceridemia and insulin resistance, respectively. Evidence is now emerging that the PPARbeta/delta; isotype is a potential pharmacological target for the treatment of disorders associated with metabolic syndrome. PPARbeta/delta; activation increases lipid catabolism in skeletal muscle, heart and adipose tissue and improves the serum lipid profile and insulin sensitivity in several animal models. In addition, PPARbeta/delta; ligands prevent weight gain and suppress macrophage-derived inflammation. These data are promising and indicate that PPARbeta/delta; ligands may become a therapeutic option for the treatment of metabolic syndrome. However, clinical trials in humans assessing the efficacy and safety of these drugs should confirm these promising perspectives in the treatment of the metabolic syndrome.Current Molecular Pharmacology 01/2009; 2(1):46-55.