title: Effects of PPARs agonists on cardiac metabolism in littermate and cardiomyocyte-specific PPAR-γ-knockout (CM-PGKO) mice.
abstract: Understanding the molecular regulatory mechanisms controlling for myocardial lipid metabolism is of critical importance for the development of new therapeutic strategies for heart diseases. The role of PPARγ and thiazolidinediones in regulation of myocardial lipid metabolism is controversial. The aim of our study was to assess the role of PPARγ on myocardial lipid metabolism and function and differentiate local/from systemic actions of PPARs agonists using cardiomyocyte-specific PPARγ -knockout (CM-PGKO) mice. To this aim, the effect of PPARγ, PPARγ/PPARα and PPARα agonists on cardiac function, intra-myocyte lipid accumulation and myocardial expression profile of genes and proteins, affecting lipid oxidation, uptake, synthesis, and storage (CD36, CPT1MIIA, AOX, FAS, SREBP1-c and ADPR) was evaluated in cardiomyocyte-specific PPARγ-knockout (CM-PGKO) and littermate control mice undergoing standard and high fat diet (HFD). At baseline, protein levels and mRNA expression of genes involved in lipid uptake, oxidation, synthesis, and accumulation of CM-PGKO mice were not significantly different from those of their littermate controls. At baseline, no difference in myocardial lipid content was found between CM-PGKO and littermate controls. In standard condition, pioglitazone and rosiglitazone do not affect myocardial metabolism while, fenofibrate treatment significantly increased CD36 and CPT1MIIA gene expression. In both CM-PGKO and control mice submitted to HFD, six weeks of treatment with rosiglitazone, fenofibrate and pioglitazone lowered myocardial lipid accumulation shifting myocardial substrate utilization towards greater contribution of glucose. In conclusion, at baseline, PPARγ does not play a crucial role in regulating cardiac metabolism in mice, probably due to its low myocardial expression. PPARs agonists, indirectly protect myocardium from lipotoxic damage likely reducing fatty acids delivery to the heart through the actions on adipose tissue. Nevertheless a direct non-PPARγ mediated mechanism of PPARγ agonist could not be ruled out.
authors.affiliation: Department of Geriatric Medicine and Metabolic Diseases, Second University of Naples, Naples, Italy.
authors.forename: Michelangela
authors.initials: M
authors.lastname: Barbieri
authors.forename: Clara
authors.initials: C
authors.lastname: Di Filippo
authors.forename: Antonietta
authors.initials: A
authors.lastname: Esposito
authors.forename: Raffaele
authors.initials: R
authors.lastname: Marfella
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Rizzo
authors.forename: Michele
authors.initials: M
authors.lastname: D'Amico
authors.forename: Franca
authors.initials: F
authors.lastname: Ferraraccio
authors.forename: Cristina
authors.initials: C
authors.lastname: Di Ronza
authors.forename: Sheng Zhong
authors.initials: SZ
authors.lastname: Duan
authors.forename: Richard M
authors.initials: RM
authors.lastname: Mortensen
authors.forename: Francesco
authors.initials: F
authors.lastname: Rossi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Paolisso
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D059305:Diet, High-Fat; D011345:Fenofibrate / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists* / Q000378:metabolism; D000077205:Pioglitazone; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D018955:CD36 Antigens; D047493:PPAR alpha; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D005947:Glucose; D011345:Fenofibrate; D000077205:Pioglitazone