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.
BACKGROUND
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.


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 PPARalpha(-/-) mice and was blunted on siRNA-mediated PPARbeta/delta knockdown in cultured cardiomyocytes. Consistent with these data, linolenic acid stimulated binding of PPARbeta/delta but not PPARalpha 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 PPARbeta/delta is part of a feedback mechanism aimed at protecting the heart against lipid overload and consequently fatty acid-induced oxidative stress.
Georgiadi
Anastasia
A
Nutrition, Metabolism and Genomics group, Wageningen University, Bomenweg 2, 6703 HD Wageningen, The Netherlands.
Lichtenstein
Laeticia
L
Degenhardt
Tatjana
T
Boekschoten
Mark V
MV
van Bilsen
Marc
M
Desvergne
Beatrice
B
Müller
Michael
M
Kersten
Sander
S
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D009202:Cardiomyopathies / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D002478:Cells, Cultured; D019610:Cytoprotection; D004041:Dietary Fats / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000633:toxicity; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000633:toxicity; D025461:Feedback, Physiological; D019787:Linoleic Acid / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D019301:Oleic Acid / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D047494:PPAR delta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048068:PPAR-beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D013997:Time Factors; D015854:Up-Regulation; D017962:alpha-Linolenic Acid / Q000378:metabolism
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D004041:Dietary Fats; D005231:Fatty Acids, Unsaturated; D047494:PPAR delta; D048068:PPAR-beta; D017962:alpha-Linolenic Acid; D019301:Oleic Acid; D019787:Linoleic Acid