Dietary stimulators of the PGC-1 superfamily and mitochondrial biosynthesis in skeletal muscle. A mini-review

Mitochondrial dysfunction has been linked to many diseases including metabolic diseases such as diabetes. Peroxisome proliferator-activated receptor gamma co-activator 1 (PGC-1) is a superfamily of transcriptional co-activators which are important precursors to mitochondrial biosynthesis found in most cells including skeletal muscle. The PGC-1 superfamily consists of three variants all of which are directly involved in controlling metabolic gene expression including those regulating fatty acid oxidation and mitochondrial proteins. In contrast to previous reviews on PGC-1, this mini-review summarizes the current knowledge of many known dietary stimulators of PGC-1 and the subsequent mitochondrial biosynthesis with associated metabolic benefit in skeletal muscle

Optimization of an enzyme-linked immunosorbent assay to screen ligand of Peroxisome proliferator-activated receptor alpha.

Peroxisome proliferator-activated receptors (PPARs) are transcription factor which directly modulate gene expression by binding to specific agonists. It has been reported that PPARalpha controls lipid metabolism, inflammation, and atherosclerosis. PPARalpha activation by PPARalpha agonist can ultimately reduce the progression of atherosclerosis and decrease the incidence of coronary heart disease. In this study, we optimized enzyme-linked immunosorbent assay (ELISA) systems in order to screen putative PPARalpha agonists. These methods are based on the activation mechanism of PPARalpha where the ligand binding to PPARalpha induces the interaction of the receptor with transcriptional co-activators. Among co-activators such as SRC-1, TIF-2, and p300, although ligand-unbound PPARalpha had more strong binding with p300 at a lower concentrations of PPARalpha, ligand-bound PPARalpha had more specific and strong binding with SRC-1. We optimized and developed a novel and useful ELISA system to screen PPARalpha agonists. Wy14,643 and linoleic acid, the well-known PPARalpha ligands, increased the binding between PPARalpha and co-activators in a ligand dose-dependent manner. In this ELISA method to screen PPARalpha ligands, the use of specific anti-PPARalpha N-terminus antibody, full-length recombinant protein of human PPARalpha but not ligand-binding domain (LBD) of human PPARalpha, and his-tagged PPARalpha recombinant proteins but not GST-fused PPARalpha recombinant proteins is the critical factors. Development of this screening system may be useful in the discovery of PPARalpha ligands from various candidates such as chemical library and phytochemicals.

Estatinas, hiperlipemia, efectos pleiotrópicos y PPAR / Statins, hyperlipemia, pleiotropic effects, and PPARS

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Potential urinary and plasma biomarkers of peroxisome proliferation in the rat: identification of N-methylnicotinamide and N-methyl-4-pyridone-3-carboxamide by 1H nuclear magnetic resonance and high performance liquid chromatography.

This study identified two potential novel biomarkers of peroxisome proliferation in the rat. Three peroxisome proliferator-activated receptor (PPAR) ligands, chosen for their high selectivity towards the PPARalpha, -delta and -gamma subtypes, were given to rats twice daily for 7 days at doses known to cause a pharmacological effect or peroxisome proliferation. Fenofibrate was used as a positive control. Daily treatment with the PPARalpha and -delta agonists produced peroxisome proliferation and liver hypertrophy. 1H nuclear magnetic resonance spectroscopy and multivariate statistical data analysis of urinary spectra from animals given the PPARalpha and -delta agonists identified two new potential biomarkers of peroxisome proliferation--N-methylnicotinamide (NMN) and N-methyl-4-pyridone-3-carboxamide (4PY)--both endproducts of the tryptophan-nicotinamide adenine dinucleotide (NAD+) pathway. After 7 days, excretion of NMN and 4PY increased 24- and three-fold, respectively, following high doses of fenofibrate. The correlation between total NMN excretion over 7 days and the peroxisome count was r=0.87 (r2=0.76). Plasma NMN, measured using a sensitive high performance liquid chromatography method, was increased up to 61-fold after 7 days' treatment with high doses of fenofibrate. Hepatic gene expression of aminocarboxymuconate-semialdehyde decarboxylase (EC 4.1.1.45) was downregulated following treatment with the PPARalpha and -delta agonists. The decrease was up to 11-fold compared with controls in the groups treated with high doses of fenofibrate. This supports the link between increased NMN and 4PY excretion and regulation of the tryptophan-NAD+ pathway in the liver. In conclusion, NMN, and possibly other metabolites in the pathway, are potential non-invasive surrogate biomarkers of peroxisome proliferation in the rat.

Receptores activados por proliferadores peroxisómicos (PPAR), metabolismo energético y aterosclerosis / Peroxysomel proliferator actived receptors (PPARs), energy metabolism and atherosclerosis

Los receptores activados por proliferadores peroxisómicos (PPAR) son una familia de factores de transcripción que pertenecen a la superfamilia de los receptores esteroides y que incluye tres subtipos: PPAR*, PPARß/* y PPAR*. Estos receptores se unen a repeticiones directas hexaméricas en forma de heterodímeros con el receptor del retinoide X*. Los PPAR regulan la expresión de una amplia variedad de genes que codifican proteínas implicadas en el metabolismo lipídico, la homeostasis energética, la diferenciación celular y la formación de tumores. En esta revisión se describen las características, regulación y los genes diana de los PPAR y se destacan sus implicaciones fisiopatológicas sobre el metabolismo de los lípidos y la glucosa, la homeostasis energética, la aterosclerosis y la diferenciación celular (AU)