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Endogenous ω-3 fatty acid production in fat-1 transgenic mice protects against experimentally induced inflammation and carcinogenesis

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dc.contributor.advisor서영준-
dc.contributor.author염혜원-
dc.date.accessioned2017-10-27T17:01:16Z-
dc.date.available2017-10-27T17:01:16Z-
dc.date.issued2017-08-
dc.identifier.other000000145382-
dc.identifier.urihttps://hdl.handle.net/10371/137020-
dc.description학위논문 (박사)-- 서울대학교 대학원 약학대학 약학과, 2017. 8. 서영준.-
dc.description.abstractOmega-6 (ω-6) and omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) are known to have opposite effects on the inflammatory and carcinogenesis processes. In general, ω-6 PUFAs promote inflammation and tumor development, whereas ω-3 PUFAs possess anti-inflammatory as well as anti-oxidative activity and enhance host immune response.
In the present study, I investigated the protective effects of ω-3 PUFAs on experimentally induced inflammation and carcinogenesis using fat-1 transgenic mice harboring ω-3 desaturase gene capable of converting ω-6 to ω-3 PUFAs. The ω-3/ω-6 PUFA ratio was significantly higher in the dorsal skin of fat-1 mice than that in the wild-type (WT) C57BL/6 mice. fat-1 mice expressed heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase-1 and their mRNA transcripts to a greater extent than did WT mice, which was attributable to the elevated activation of nuclear factor erythroid-related factor 2 (Nrf2) responsible for upregulation of cytoprotective and stress-responsive proteins.
Exposure to solar radiation, especially ultraviolet B (UVB), is the most prevalent cause of skin photocarcinogenesis. Upon single exposure to UVB (500 mJ/cm2) irradiation, fat¬-1 mice exhibited a significantly lower degree of skin inflammation and phototoxicity and the expression of the pro-inflammatory enzyme, cyclooxygenases-2 (COX-2) as compared to those observed in WT mouse skin. The protection of fat-1 mice from UVB-induced skin inflammation was associated with decreased phosphorylation of signal transducer and activator of transcription 3 (STAT3), one of the major pro-inflammatory transcription factors.
To determine whether the elevated ω-3 PUFA level also protects against UVB-induced skin papillomagenesis, hairless fat-1−/− and fat-1+/− mice were generated by cross-breeding of male fat-1+/− transgenic mice with female SKH-1 hairless mice. After repeated UVB irradiation (180 mJ/cm2) thrice a week for 23 weeks, the incidence and the multiplicity of papillomas were markedly reduced in the fat-1+/− group as compared to the fat-1−/− group. Moreover, the expression of COX-2 and activation of STAT3 in papillomas from fat-1+/− mice were significantly lower than those found in UVB-irradiated fat-1−/− mice.
In another study, I also found that an increased ω-3 PUFA tissue status in the fat-1 mice led to effective protection against inflammatory tissue injury in colitis induced by 2,4,6-trinitrobenzene sulfonic acid. The endogenous increase in ω-3 PUFAs in fat-1 mice lso attenuated lipid peroxidation (malondialdehyde) and protein oxidation (4-hydroxy-2-nonenal). The observed protection against inflammatory and oxidative tissue damages in the fat-1 mouse colon was associated with decreased nuclear factor kappa B (NF-kappaB) activity and expression of COX-2 and with elevated activation of Nrf2 and expression of its target gene, ho-1.
Taken together, these observations indicate that functional fat-1 potentiates cellular defense against experimentally induced inflammation and tumor development through elevated activation of Nrf2 and subsequent upregulation of cytoprotective gene expression as well as suppression of pro-inflammatory signaling mediated by STAT3 and/or NF-kappaB.
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dc.description.tableofcontentsChapter Ⅰ 1
1. Introduction 2
2. The health beneficial effects associated with ω-3 PUFAs 6
3. The fat-1 transgenic mouse 10
Statement of Purpose 12
Chapter Ⅱ 13
1. Abstract 14
2. Introduction 16
3. Materials and Methods 20
4. Results 26
5. Discussion 41
Chapter Ⅲ 45
1. Abstract 46
2. Introduction 48
3. Materials and Methods 51
4. Results 61
5. Discussion 86
Chapter Ⅳ 92
1. Abstract 93
2. Introduction 95
3. Materials and Methods 98
4. Results 104
5. Discussion 118
Conclusion 121
References 123
Abstract in Korean 151
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dc.formatapplication/pdf-
dc.format.extent3621370 bytes-
dc.format.mediumapplication/pdf-
dc.language.isoen-
dc.publisher서울대학교 대학원-
dc.subject2-
dc.subject4-
dc.subject6-Trinitrobenzene sulfonic acid-
dc.subjectColitis-
dc.subjectfat-1 transgenic mice-
dc.subjectInflammation-
dc.subjectNF-kappaB-
dc.subjectNrf2-
dc.subjectOmega-3 polyunsaturated fatty acids-
dc.subjectPhotocarcinogenesis-
dc.subjectSTAT3-
dc.subjectUltraviolet B-
dc.subject.ddc615-
dc.titleEndogenous ω-3 fatty acid production in fat-1 transgenic mice protects against experimentally induced inflammation and carcinogenesis-
dc.typeThesis-
dc.description.degreeDoctor-
dc.contributor.affiliation약학대학 약학과-
dc.date.awarded2017-08-
Appears in Collections:
College of Pharmacy (약학대학)Dept. of Pharmacy (약학과)Theses (Ph.D. / Sc.D._약학과)
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