title: Suppressed liver tumorigenesis in fat-1 mice with elevated omega-3 fatty acids is associated with increased omega-3 derived lipid mediators and reduced TNF-α.
abstract: Liver tumors, particularly hepatocellular carcinoma (HCC), are a major cause of morbidity and mortality worldwide. The development of HCC is mostly associated with chronic inflammatory liver disease of various etiologies. Previous studies have shown that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) dampen inflammation in the liver and decrease formation of tumor necrosis factor (TNF)-α. In this study, we used the fat-1 transgenic mouse model, which endogenously forms n-3 PUFA from n-6 PUFA to determine the effect of an increased n-3 PUFA tissue status on tumor formation in the diethylnitrosamine (DEN)-induced liver tumor model. Our results showed a decrease in tumor formation, in terms of size and number, in fat-1 mice compared with wild-type littermates. Plasma TNF-α levels and liver cyclooxygenase-2 expression were markedly lower in fat-1 mice. Furthermore, there was a decreased fibrotic activity in the livers of fat-1 mice. Lipidomics analyses of lipid mediators revealed significantly increased levels of the n-3 PUFA-derived 18-hydroxyeicosapentaenoic acid (18-HEPE) and 17-hydroxydocosahexaenoic acid (17-HDHA) in the livers of fat-1 animals treated with DEN. In vitro experiments showed that 18-HEPE and 17-HDHA could effectively suppress lipopolysacharide-triggered TNF-α formation in a murine macrophage cell line. The results of this study provide evidence that an increased tissue status of n-3 PUFA suppresses liver tumorigenesis, probably through inhibiting liver inflammation. The findings also point to a potential anticancer role for the n-3 PUFA-derived lipid mediators 18-HEPE and 17-HDHA, which can downregulate the important proinflammatory and proproliferative factor TNF-α.
authors.affiliation: Laboratory for Lipid Medicine and Technology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. karsten.weylandt@charite.de
authors.forename: Karsten H
authors.initials: KH
authors.lastname: Weylandt
authors.forename: Lena F
authors.initials: LF
authors.lastname: Krause
authors.forename: Beate
authors.initials: B
authors.lastname: Gomolka
authors.forename: Cheng-Ying
authors.initials: CY
authors.lastname: Chiu
authors.forename: Süleyman
authors.initials: S
authors.lastname: Bilal
authors.forename: Anja
authors.initials: A
authors.lastname: Nadolny
authors.forename: Simon F
authors.initials: SF
authors.lastname: Waechter
authors.forename: Andreas
authors.initials: A
authors.lastname: Fischer
authors.forename: Michael
authors.initials: M
authors.lastname: Rothe
authors.forename: Jing X
authors.initials: JX
authors.lastname: Kang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000517:prevention & control*; D002478:Cells, Cultured; D002849:Chromatography, Gas; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D044943:Fatty Acid Desaturases / Q000502:physiology*; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000517:prevention & control*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D015525:Fatty Acids, Omega-3; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C466741:fat-1 protein, C elegans; D004281:Docosahexaenoic Acids; C062894:17-hydroxy-4,7,10,13,15,19-docosahexaenoic acid; D044943:Fatty Acid Desaturases