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.

Fenofibrate inhibits atrial metabolic remodelling in atrial fibrillation through PPAR‐α/sirtuin 1/PGC‐1α pathway

“…Fenofibrate increases the expression of fatty acid β‐oxidation enzymes in the fatty liver (Seo et al , ) and reduces SREBP1c expression (Barbieri et al , ). Both studies of AF indicated a significant down‐regulation of transcripts and proteins involved in lipid metabolism (Barth et al , ; Tu et al , ).…”

Post mortem evaluation of inflammation, oxidative stress, and PPARγ activation in a nonhuman primate model of cardiac sympathetic neurodegeneration

“…In non-diabetic, non-obese humans and animal models, pioglitazone has repeatedly been demonstrated to increase CD36 mRNA or protein expression in multiple cell types including skeletal muscle [65], immune cells [66][67][68][69][70], endothelial cells [70], hepatic stellate cells [71], and adipose tissue [72]. A small number of studies have shown no increase in CD36 following pioglitazone in normal human adipose tissue [73], normal rat liver [74], and, interestingly, normal mouse cardiomyocytes [75]. It is currently unclear why the impact of pioglitazone on cardiomyocyte CD36 is different between our study and research carried out in mice [75].…”

“…A small number of studies have shown no increase in CD36 following pioglitazone in normal human adipose tissue [73], normal rat liver [74], and, interestingly, normal mouse cardiomyocytes [75]. It is currently unclear why the impact of pioglitazone on cardiomyocyte CD36 is different between our study and research carried out in mice [75]. In addition to a possible species difference, it should be noted that the previous publication quantified CD36 mRNA level, in contrast to the current study, which investigated CD36 protein immunoreactivity and subcellular localization.…”

PPARs: Protectors or Opponents of Myocardial Function?

“…Global PPAR γ −/− is lethal and the embryos have cardiac abnormalities caused by placental defects [ 126 ]. Cardiomyocyte-specific PPAR γ −/− mice develop cardiac hypertrophy with preserved systolic cardiac function and most likely have normal cardiac metabolism [ 127 – 129 ]. Increased NF κ B expression [ 127 ] or macrophage infiltration [ 128 ] might contribute to the development of hypertrophy.…”

“…Lipid redistribution and decreased mitochondrial and ER stress might contribute to the improved cardiac function and survival. In cardiomyocyte PPAR δ −/− mice, treatment with the PPAR α agonist fenofibrate increased Cd36 and Cpt1 gene expression but did not affect myocardial lipid content [ 129 ].…”