Peroxisome proliferator-activated receptor β/δ activation inhibits hypertrophy in neonatal rat cardiomyocytes

Objective: Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is the predominant PPAR subtype in cardiac cells and plays a prominent role in the regulation of cardiac lipid metabolism. However, the role of PPARβ/δ activators in cardiac hypertrophy is not yet known. Methods and Results: In cultured neonatal rat cardiomyocytes, the selective PPARβ/δ activator L-165041 (10 μmol/L) inhibited phenylephrine (PE)-induced protein synthesis ([3H]leucine uptake), induction of the fetal-type gene atrial natriuretic factor (ANF) and cardiac myocyte size. Induction of cardiac hypertrophy by PE stimulation also led to a reduction in the transcript levels of both muscle-type carnitine palmitoyltransferase (50%, P<0.05) and pyruvatedehydrogenase kinase 4 (30%, P<0.05), and these changes were reversed in the presence of the PPARβ/δ agonist L-165041. Stimulation of neonatal rat cardiomyocytes with PE and embryonic rat heart-derived H9c2 cells with lipopolysaccharide (LPS) enhanced the expression of the nuclear factor (NF)-κB-target gene monocyte chemoattractant protein 1 (MCP-1). The induction of MCP-1 was reduced in the presence of L-165041, suggesting that this compound prevented NF-κB activation. Electrophoretic mobility shift assay (EMSA) revealed that L-165041 significantly decreased LPS-stimulated NF-κB binding activity in H9c2 myotubes. Finally, coimmunoprecipitation studies showed that L-165041 strongly enhanced the physical interaction between PPARβ/δ and the p65 subunit of NF-κB, suggesting that increased association between these two proteins is the mechanism responsible for antagonizing NF-κB activation by PPARβ/δ activators. Conclusion: These results suggest that PPARβ/δ activation inhibits PE-induced cardiac hypertrophy and LPS-induced NF-κB activatio

Inhibition of Cardiac Hypertrophy by Triflusal (4-Trifluoromethyl Derivative of Salicylate) and Its Active Metabolite

ABSTRACT The nuclear factor (NF)-B signaling pathway is an important intracellular mediator of cardiac hypertrophy. The aim of the present study was to determine whether triflusal (2-acetoxy-4-trifluoromethylbenzoic acid), a salicylate derivative used as antiplatelet agent, and its active metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) inhibit cardiac hypertrophy in vitro and in vivo by blocking the NF-B signaling pathway. In cultured neonatal rat cardiomyocytes, HTB (300 M, a concentration reached in clinical use) inhibited phenylephrine (PE)-induced protein synthesis ([ 3 H]leucine uptake), induction of the fetal-type gene atrial natriuretic factor (ANF), and sarcomeric disorganization. Assessment of the effects of triflusal in pressure overload-induced cardiac hypertrophy by aortic banding resulted in a significant reduction in the ratio of heart weight to body weight and in a reduction of the mRNA levels of the cardiac hypertrophy markers ANF and ␣-actinin compared with untreated banded rats. Electrophoretic mobility shift assay revealed an increase in the NF-B binding activity in cardiac nuclear extracts of banded rats that was prevented by triflusal treatment. It is noteworthy that banded rats treated with oral triflusal, compared with untreated rats, showed enhanced protein levels of IB␣, which forms a cytoplasmic inactive complex with the p65-p50 heterodimeric complex. Finally, HTB increased phospho-IB␣ levels in neonatal cardiomyocytes and inhibited proteosome activity, suggesting that this drug prevented proteosome-mediated degradation of IB␣. These results indicate that triflusal, a drug with a well characterized pharmacological and safety profile currently used as antiplatelet, inhibits cardiomyocyte growth by interfering with the NF-B signaling pathway through a post-transcriptional mechanism involving reduced-proteosome degradation of IB␣. Cardiac hypertrophy is a response of the heart to a wide range of extrinsic stimuli, such as arterial hypertension, valvular heart disease, myocardial infarction, and cardiomyopathy. Although this process is initially compensatory for an increase workload, its prolongation frequently results in congestive heart failure, arrhythmia, and sudden deat

The lipid sensor GPR120 promotes brown fat activation and FGF21 release from adipocytes

The thermogenic activity of brown adipose tissue (BAT) and browning of white adipose tissue are important components of energy expenditure. Here we show that GPR120, a receptor for polyunsaturated fatty acids, promotes brown fat activation. Using RNA-seq to analyse mouse BAT transcriptome, we find that the gene encoding GPR120 is induced by thermogenic activation. We further show that GPR120 activation induces BAT activity and promotes the browning of white fat in mice, whereas GRP120-null mice show impaired cold-induced browning. Omega-3 polyunsaturated fatty acids induce brown and beige adipocyte differentiation and thermogenic activation, and these effects require GPR120. GPR120 activation induces the release of fibroblast growth factor-21 (FGF21) by brown and beige adipocytes, and increases blood FGF21 levels. The effects of GPR120 activation on BAT activation and browning are impaired in FGF21-null mice and cells. Thus, the lipid sensor GPR120 activates brown fat via a mechanism that involves induction of FGF21.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

SIRT1 Controls the Transcription of the Peroxisome Proliferator-activated Receptor-γ Co-activator-1α (PGC-1α) Gene in Skeletal Muscle through the PGC-1α Autoregulatory Loop and Interaction with MyoD*

Peroxisome proliferator activated receptor-γ co-activator-1α (PGC-1α) is a transcriptional co-activator that coordinately regulates the expression of distinct sets of metabolism-related genes in different tissues. Here we show that PGC-1α expression is reduced in skeletal muscles from mice lacking the sirtuin family deacetylase SIRT1. Conversely, SIRT1 activation or overexpression in differentiated C2C12 myotubes increased PGC-1α mRNA expression. The transcription-promoting effects of SIRT1 occurred through stimulation of PGC-1α promoter activity and were enhanced by co-transfection of myogenic factors, such as myocyte enhancer factor 2 (MEF2) and, especially, myogenic determining factor (MyoD). SIRT1 bound to the proximal promoter region of the PGC-1α gene, an interaction potentiated by MEF2C or MyoD, which also interact with this region. In the presence of MyoD, SIRT1 promoted a positive autoregulatory PGC-1α expression loop, such that overexpression of PGC-1α increased PGC-1α promoter activity in the presence of co-expressed MyoD and SIRT1. Chromatin immunoprecipitation showed that SIRT1 interacts with PGC-1α promoter and increases PGC-1α recruitment to its own promoter region. Immunoprecipitation assays further showed that SIRT1-PGC-1α interactions are enhanced by MyoD. Collectively, these data indicate that SIRT1 controls PGC-1α gene expression in skeletal muscle and that MyoD is a key mediator of this action. The involvement of MyoD in SIRT1-dependent PGC-1α expression may help to explain the ability of SIRT1 to drive muscle-specific gene expression and metabolism. Autoregulatory control of PGC-1α gene transcription seems to be a pivotal mechanism for conferring a transcription-activating response to SIRT1 in skeletal muscle