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


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.


CONCLUSIONS
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.
Department of Pharmacology and Therapeutic Chemistry, IBUB (Institut de Biomedicina de la Universitat de Barcelona), CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Faculty of Pharmacy, University of Barcelona, Diagonal 643, Barcelona E-08028, Spain.
Xavier
X
Palomer
Department of Pharmacology and Therapeutic Chemistry, IBUB (Institut de Biomedicina de la Universitat de Barcelona), CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Faculty of Pharmacy, University of Barcelona, Diagonal 643, Barcelona E-08028, Spain.
Eva
E
Capdevila-Busquets
Department of Pharmacology and Therapeutic Chemistry, IBUB (Institut de Biomedicina de la Universitat de Barcelona), CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Faculty of Pharmacy, University of Barcelona, Diagonal 643, Barcelona E-08028, Spain.
Gaia
G
Botteri
Department of Pharmacology and Therapeutic Chemistry, IBUB (Institut de Biomedicina de la Universitat de Barcelona), CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Faculty of Pharmacy, University of Barcelona, Diagonal 643, Barcelona E-08028, Spain.
Laia
L
Salvadó
Department of Pharmacology and Therapeutic Chemistry, IBUB (Institut de Biomedicina de la Universitat de Barcelona), CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Faculty of Pharmacy, University of Barcelona, Diagonal 643, Barcelona E-08028, Spain.
Emma
E
Barroso
Department of Radiation Oncology, Columbia University, P&S 11-451, 630 West 168th Street, New York, NY 10032, USA.
Mercy M
MM
Davidson
Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Quartier UNIL-Sorge, Bâtiment Génopode, CH-1015 Lausanne, Switzerland.
Liliane
L
Michalik
Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Quartier UNIL-Sorge, Bâtiment Génopode, CH-1015 Lausanne, Switzerland; Lee Kong Chian School of Medicine, Nanyang Technological University, School of Nursing Building, SGH, Block C, #01-01, 9 Hospital Drive, Singapore 169612, Singapore.
Walter
W
Wahli
Department of Pharmacology and Therapeutic Chemistry, IBUB (Institut de Biomedicina de la Universitat de Barcelona), CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Faculty of Pharmacy, University of Barcelona, Diagonal 643, Barcelona E-08028, Spain. Electronic address: mvazquezcarrera@ub.edu.
Manuel
M
Vázquez-Carrera
D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects*; D047494:PPAR delta / Q000494:pharmacology*; D048068:PPAR-beta / Q000494:pharmacology*; D010168:Palmitates / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology
C425931:GW 501516; D047494:PPAR delta; D048068:PPAR-beta; D010168:Palmitates; D013844:Thiazoles
Autophagy; Diabetic cardiomyopathy; Endoplasmic reticulum stress; PPARβ/δ