title: 4-Hydroxy hexenal derived from dietary n-3 polyunsaturated fatty acids induces anti-oxidative enzyme heme oxygenase-1 in multiple organs.
abstract: It has recently been reported that expression of heme oxygenase-1 (HO-1) plays a protective role against many diseases. Furthermore, n-3 polyunsaturated fatty acids (PUFAs) were shown to induce HO-1 expression in several cells in vitro, and in a few cases also in vivo. However, very few reports have demonstrated that n-3 PUFAs induce HO-1 in vivo. In this study, we examined the effect of fish-oil dietary supplementation on the distribution of fatty acids and their peroxidative metabolites and on the expression of HO-1 in multiple tissues (liver, kidney, heart, lung, spleen, intestine, skeletal muscle, white adipose, brown adipose, brain, aorta, and plasma) of C57BL/6 mice. Mice were divided into 4 groups, and fed a control, safflower-oil, and fish-oil diet for 3 weeks. One group was fed a fish-oil diet for just 1 week. The concentration of fatty acids, 4-hydroxy hexenal (4-HHE), and 4-hydroxy nonenal (4-HNE), and the expression of HO-1 mRNA were measured in the same tissues. We found that the concentration of 4-HHE (a product of n-3 PUFAs peroxidation) and expression of HO-1 mRNA were significantly increased after fish-oil treatment in most tissues. In addition, these increases were paralleled by an increase in the level of docosahexaenoic acid (DHA) but not eicosapentaenoic acid (EPA) in each tissue. These results are consistent with our previous results showing that DHA induces HO-1 expression through 4-HHE in vascular endothelial cells. In conclusion, we hypothesize that the HO-1-mediated protective effect of the fish oil diet may be through production of 4-HHE from DHA but not EPA in various tissues.
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga 520-2192, Japan; Osaka Laboratory, JCL Bioassay Corporation, 5-16-26, Minamisuita, Suita-shi, Osaka 564-0043, Japan.
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Nakagawa
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga 520-2192, Japan. Electronic address: morino@belle.shiga-med.ac.jp.
authors.forename: Katsutaro
authors.initials: K
authors.lastname: Morino
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga 520-2192, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ugi
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga 520-2192, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ishikado
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga 520-2192, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga 520-2192, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sato
authors.affiliation: Osaka Laboratory, JCL Bioassay Corporation, 5-16-26, Minamisuita, Suita-shi, Osaka 564-0043, Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Konno
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga 520-2192, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Nemoto
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga 520-2192, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Kusunoki
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga 520-2192, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Sekine
authors.affiliation: Osaka Laboratory, JCL Bioassay Corporation, 5-16-26, Minamisuita, Suita-shi, Osaka 564-0043, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sunagawa
authors.affiliation: Osaka Laboratory, JCL Bioassay Corporation, 5-16-26, Minamisuita, Suita-shi, Osaka 564-0043, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Kawamura
authors.affiliation: Osaka Laboratory, JCL Bioassay Corporation, 5-16-26, Minamisuita, Suita-shi, Osaka 564-0043, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Inoue
authors.affiliation: Department of Diabetes and Endocrine Medicine, Division of Human and Environmental Sciences, Kagoshima University, Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Nishio
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga 520-2192, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maegawa
mesh_terms: D000447:Aldehydes / Q000097:blood / Q000378:metabolism*; D000818:Animals; D016718:Arachidonic Acid / Q000097:blood; D004281:Docosahexaenoic Acids / Q000097:blood; D015118:Eicosapentaenoic Acid / Q000097:blood; D004790:Enzyme Induction; D015525:Fatty Acids, Omega-3 / Q000097:blood / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D000447:Aldehydes; D015525:Fatty Acids, Omega-3; D012333:RNA, Messenger; C063409:4-hydroxyhexenal; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D015118:Eicosapentaenoic Acid; D051547:Heme Oxygenase-1; C027576:4-hydroxy-2-nonenal
keywords: 4-Hydroxy hexenal; Docosahexaenoic acid (DHA); Heme oxygenase-1; Nuclear factor erythroid 2-related factor 2 (Nrf2); n-3 Polyunsaturated fatty acids (PUFAs)