title: 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.
abstract: 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.
authors.affiliation: Nutrition, Metabolism and Genomics group, Wageningen University, Bomenweg 2, 6703 HD Wageningen, The Netherlands.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Georgiadi
authors.forename: Laeticia
authors.initials: L
authors.lastname: Lichtenstein
authors.forename: Tatjana
authors.initials: T
authors.lastname: Degenhardt
authors.forename: Mark V
authors.initials: MV
authors.lastname: Boekschoten
authors.forename: Marc
authors.initials: M
authors.lastname: van Bilsen
authors.forename: Beatrice
authors.initials: B
authors.lastname: Desvergne
authors.forename: Michael
authors.initials: M
authors.lastname: Müller
authors.forename: Sander
authors.initials: S
authors.lastname: Kersten
mesh_terms: 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
chemical_list: 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