Induction of Cardiac Angptl4 by Dietary Fatty Acids Is Mediated by Peroxisome Proliferator-Activated Receptor beta/delta and Protects Against Fatty Acid-Induced Oxidative Stress

Rationale: Although dietary fatty acids are a major fuel for the heart, little is known about the direct effects of dietary fatty acids on gene regulation in the intact heart. Objective: To study the effect of dietary fatty acids on cardiac gene expression and explore the functional consequences. Methods and Results: Oral administration of synthetic triglycerides composed of one single fatty acid altered cardiac expression of numerous genes, many of which are involved in the oxidative stress response. The gene most significantly and consistently upregulated by dietary fatty acids encoded Angiopoietin-like protein (Angptl)4, a circulating inhibitor of lipoprotein lipase expressed by cardiomyocytes. Induction of Angptl4 by the fatty acid linolenic acid was specifically abolished in peroxisome proliferator-activated receptor (PPAR)beta/delta(-/-) and not PPAR alpha(-/-) mice and was blunted on siRNA-mediated PPAR beta/delta knockdown in cultured cardiomyocytes. Consistent with these data, linolenic acid stimulated binding of PPAR beta/delta but not PPAR alpha to the Angptl4 gene. Upregulation of Angptl4 resulted in decreased cardiac uptake of plasma triglyceride-derived fatty acids and decreased fatty acid-induced oxidative stress and lipid peroxidation. In contrast, Angptl4 deletion led to enhanced oxidative stress in the heart, both after an acute oral fat load and after prolonged high fat feeding. Conclusions: Stimulation of cardiac Angptl4 gene expression by dietary fatty acids and via PPAR beta/delta is part of a feedback mechanism aimed at protecting the heart against lipid overload and consequently fatty acid-induced oxidative stress. (Circ Res. 2010; 106: 1712-1721.)