title: ω-6 (18:2) and ω-3 (18:3) fatty acids in reconstituted high-density lipoproteins show different functionality of anti-atherosclerotic properties and embryo toxicity.
abstract: Among unsaturated fatty acids, epidemiologic studies have demonstrated that ω-6 (linoleic acid) and ω-3 (linolenic acid) fatty acids show different associations with risk of cardiovascular disease (CVD), although its molecular mechanisms remain unclear. To determine why consumption of ω-3 fatty acid is associated with lower risk of CVD, we investigated the biological functions of ω-6 (linoleic acid) and ω-3 (linolenic acid) in reconstituted HDL (rHDL) after encapsulation using human cells and zebrafish embryo. Apolipoprotein A-I (apoA-I) is the principal protein behind the beneficial functions of HDL, which include potent anti-oxidant, anti-inflammatory, and anti-atherosclerotic activities in blood. Several rHDLs were synthesized with apoA-I and different molar ratio of ω-6 or ω-3 fatty acid. Both fatty acids showed similar solubility in rHDL up to a molar ratio of 95:5:1:10 (palmitoyloleoyl phosphatidylcholine:cholesterol:apoA-I:fatty acid). Although both rHDL showed similar structural properties and α-helical contents, ω-6-rHDL showed loss of anti-oxidant ability against LDL oxidation. Uptake of acetylated LDL into macrophages was inhibited by ω-3-rHDL but not ω-6-rHDL, suggesting that ω-6-rHDL has higher pro-atherosclerotic activity. ω-3-rHDL showed more enhanced cholesterol efflux activity with less accumulation of triglyceride in the macrophage. ω-6-rHDL caused more senescence in human dermal fibroblast cells with cytotoxicity, while ω-3-rHDL treatment inhibited the senescence. In zebrafish embryo survivability, ω-3-rHDL-injected embryos showed 86±3% survival, whereas ω-6-rHDL-injected ones showed 72±2% survival as well as an elevated inflammatory response in zebrafish embryos. In conclusion, ω-6-rHDL and ω-3-rHDL show different physiological activities in atherosclerosis, inflammation, and cellular senescence.
authors.affiliation: School of Biotechnology, Yeungnam University, Gyeongsan, 712-749, Republic of Korea; Research Institute of Protein Sensor, Yeungnam University, Gyeongsan, 712-749, Republic of Korea; BK21plus Program Serum Biomedical Research and Education Team, Yeungnam University, Gyeongsan, 712-749, Republic of Korea.
authors.forename: Ki-Hoon
authors.initials: KH
authors.lastname: Park
authors.affiliation: School of Biotechnology, Yeungnam University, Gyeongsan, 712-749, Republic of Korea; Research Institute of Protein Sensor, Yeungnam University, Gyeongsan, 712-749, Republic of Korea; BK21plus Program Serum Biomedical Research and Education Team, Yeungnam University, Gyeongsan, 712-749, Republic of Korea.
authors.forename: Jae-Yong
authors.initials: JY
authors.lastname: Kim
authors.affiliation: School of Biotechnology, Yeungnam University, Gyeongsan, 712-749, Republic of Korea; Research Institute of Protein Sensor, Yeungnam University, Gyeongsan, 712-749, Republic of Korea; BK21plus Program Serum Biomedical Research and Education Team, Yeungnam University, Gyeongsan, 712-749, Republic of Korea.
authors.forename: Inho
authors.initials: I
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu, 705-717, Republic of Korea.
authors.forename: Jae-Ryong
authors.initials: JR
authors.lastname: Kim
authors.affiliation: School of Biotechnology, Yeungnam University, Gyeongsan, 712-749, Republic of Korea; Research Institute of Protein Sensor, Yeungnam University, Gyeongsan, 712-749, Republic of Korea; BK21plus Program Serum Biomedical Research and Education Team, Yeungnam University, Gyeongsan, 712-749, Republic of Korea. Electronic address: chok@yu.ac.kr.
authors.forename: Kyung-Hyun
authors.initials: KH
authors.lastname: Cho
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D016632:Apolipoprotein A-I / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000517:prevention & control*; D016922:Cellular Senescence; D002942:Circular Dichroism; D005347:Fibroblasts / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007249:Inflammation; D019787:Linoleic Acid / Q000737:chemistry*; D008055:Lipids / Q000737:chemistry; D008075:Lipoproteins, HDL / Q000737:chemistry*; D008077:Lipoproteins, LDL / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism; D010100:Oxygen / Q000737:chemistry; D010587:Phagocytosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D014364:Tryptophan / Q000737:chemistry; D015027:Zebrafish; D017962:alpha-Linolenic Acid / Q000737:chemistry*
chemical_list: C505693:APOA1 protein, human; D000975:Antioxidants; D016632:Apolipoprotein A-I; D008055:Lipids; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; C032629:acetyl-LDL; C099252:oxidized low density lipoprotein; D017962:alpha-Linolenic Acid; D014364:Tryptophan; D019787:Linoleic Acid; D010100:Oxygen
keywords: Atherosclerosis; Inflammation; Linoleic acid (ω-6); Linolenic acid (ω-3); Reconstituted HDL; Zebrafish