PPARβ/δ attenuates palmitate-induced endoplasmic reticulum stress and induces autophagic markers in human cardiac cells

Int J Cardiol. 2014 Jun 1;174(1):110-8. doi: 10.1016/j.ijcard.2014.03.176. Epub 2014 Apr 8.


Background: Chronic endoplasmic reticulum (ER) stress contributes to the apoptotic cell death in the myocardium, thereby playing a critical role in the development of cardiomyopathy. ER stress has been reported to be induced after high-fat diet feeding in mice and also after saturated fatty acid treatment in vitro. Therefore, since several studies have shown that peroxisome proliferator-activated receptor (PPAR)β/δ inhibits ER stress, the main goal of this study consisted in investigating whether activation of this nuclear receptor was able to prevent lipid-induced ER stress in cardiac cells.

Methods and results: Wild-type and transgenic mice with reduced PPARβ/δ expression were fed a standard diet or a high-fat diet for two months. For in vitro studies, a cardiomyocyte cell line of human origin, AC16, was treated with palmitate and the PPARβ/δ agonist GW501516. Our results demonstrate that palmitate induced ER stress in AC16 cells, a fact which was prevented after PPARβ/δ activation with GW501516. Interestingly, the effect of GW501516 on ER stress occurred in an AMPK-independent manner. The most striking result of this study is that GW501516 treatment also upregulated the protein levels of beclin 1 and LC3II, two well-known markers of autophagy. In accordance with this, feeding on a high-fat diet or suppression of PPARβ/δ in knockout mice induced ER stress in the heart. Moreover, PPARβ/δ knockout mice also displayed a reduction in autophagic markers.

Conclusion: Our data indicate that PPARβ/δ activation might be useful to prevent the harmful effects of ER stress induced by saturated fatty acids in the heart by inducing autophagy.

Keywords: Autophagy; Diabetic cardiomyopathy; Endoplasmic reticulum stress; PPARβ/δ.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / drug effects*
  • Cells, Cultured
  • Endoplasmic Reticulum Stress / drug effects*
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Myocytes, Cardiac / drug effects*
  • PPAR delta / pharmacology*
  • PPAR-beta / pharmacology*
  • Palmitates / pharmacology*
  • Thiazoles / pharmacology


  • GW 501516
  • PPAR delta
  • PPAR-beta
  • Palmitates
  • Thiazoles