Docosahexaenoic acid (DHA) blunts liver injury by conversion to protective lipid mediators: protectin D1 and 17S-hydroxy-DHA.
Docosahexaenoic acid (DHA) is a omega-3 essential fatty acid that reduces the incidence and severity of a number of diseases. Recently, a novel series of DHA-derived lipid mediators with potent protective actions has been identified. In this study we demonstrate that dietary amplification of these DHA-derived products protects the liver from necroinflammatory injury. In vitro, supplementation of hepatocytes with DHA significantly reduced hydrogen peroxide-induced DNA damage, evaluated by the "comet assay," and oxidative stress, determined by measurement of malondialdehyde levels. In vivo, dietary supplementation of mice with DHA ameliorated carbon tetrachloride-induced necroinflammatory damage. In addition, hepatic cyclooxygenase-2 expression and PGE2 levels were significantly reduced in mice fed DHA-enriched diets. In these animals, increased hepatic formation of DHA-derived lipid mediators (i.e., 17S-hydroxy-DHA (17S-HDHA) and protectin D1) was detected by HPLC-gas chromatography/mass spectrometry analysis. Consistent with these findings, synthetic 17-HDHA abrogated genotoxic and oxidative damage in hepatocytes and decreased TNF-alpha release and 5-lipoxygenase expression in macrophages. In a transactivation assay, 17-HDHA acted in a concentration-dependent manner as a PPARgamma agonist. Taken together, these findings identify a potential role for DHA-derived products, specifically 17S-HDHA and protectin D1, in mediating the protective effects of dietary DHA in necroinflammatory liver injury.
González-Périz
Ana
A
Department of Biochemistry and Molecular Genetics, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona School of Medicine, Barcelona 08036, Spain.
Planagumà
Anna
A
Gronert
Karsten
K
Miquel
Rosa
R
López-Parra
Marta
M
Titos
Esther
E
Horrillo
Raquel
R
Ferré
Natàlia
N
Deulofeu
Ramon
R
Arroyo
Vicente
V
Rodés
Juan
J
Clària
Joan
J
D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury; D004032:Diet; D004041:Dietary Fats; D019587:Dietary Supplements; D004281:Docosahexaenoic Acids / Q000737:chemistry* / Q000378:metabolism*; D005227:Fatty Acids; D005786:Gene Expression Regulation; D008099:Liver / Q000378:metabolism*; D008107:Liver Diseases / Q000517:prevention & control*; D008297:Male; D051379:Mice
D004041:Dietary Fats; D005227:Fatty Acids; C487679:protectin D1; D004281:Docosahexaenoic Acids; C062894:17-hydroxy-4,7,10,13,15,19-docosahexaenoic acid; D002251:Carbon Tetrachloride