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IGF1 suppresses cholesterol accumulation in the liver of growth hormone deficient mice via the activation of ABCA1
https://kagawa-u.repo.nii.ac.jp/records/343
https://kagawa-u.repo.nii.ac.jp/records/343350e42fb-eab8-4457-b7a3-5387ea43a4c3
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本文 (3.1 MB)
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内容の要旨 (66.8 kB)
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審査の結果の要旨 (86.2 kB)
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| Item type | 学位論文 / Thesis or Dissertation(1) | |||||||||||||
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| 公開日 | 2019-01-30 | |||||||||||||
| タイトル | ||||||||||||||
| タイトル | IGF1 suppresses cholesterol accumulation in the liver of growth hormone deficient mice via the activation of ABCA1 | |||||||||||||
| 言語 | en | |||||||||||||
| 言語 | ||||||||||||||
| 言語 | eng | |||||||||||||
| 資源タイプ | ||||||||||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_db06 | |||||||||||||
| 資源タイプ | doctoral thesis | |||||||||||||
| アクセス権 | ||||||||||||||
| アクセス権 | open access | |||||||||||||
| アクセス権URI | http://purl.org/coar/access_right/c_abf2 | |||||||||||||
| 著者 |
福長, 健作
× 福長, 健作
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| 抄録 | ||||||||||||||
| 内容記述タイプ | Abstract | |||||||||||||
| 内容記述 | Abstract Recently, several clinical studies have suggested that adult growth hormone (GH) deficiency that also has low concentration of IGF1 is associated with an increased prevalence of fatty liver (FL). ATP-binding cassette transporter A1 (ABCA1) is a pivotal regulator of lipid efflux from cells to apolipoproteins and plays an important role on formation of FL. In this study, we determined the effects of IGF1 on ABCA1 expression in GH-deficient mice to clarify its effects on FL. Western blotting, real-time PCR, and a luciferase assay were employed to examine the effect of IGF1. The binding of FoxO1 to the ABCA1 promoter was assessed by chromatin immunoprecipitation (ChIP) assay. Cholesterol accumulation was analyzed by Oil Red O stain and cholesterol content measurement. We confirmed that IGF1 upregulated the ABCA1 expression. The activity of a reporter construct containing the ABCA1 promoter was induced by IGF1, and this effect was blocked by LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K). Constitutively active Akt stimulated the ABCA1 promoter activity, and a dominant-negative mutant of Akt or mutagenesis of the FoxO1 response element abolished the effect of IGF1. A ChIP assay indicated that FoxO1 mediated IGF1 transcriptional activity by directly binding to the ABCA1 promoter region. For in vivo experiments, we used an inhibitor for the GH receptor (Pegvisomant) to reduce the IGF1 level. A high-fat diet induced FL in mice (C57BL/6J) given Pegvisomant treatment. IGF1 treatment stimulated ABCA1 expression to improve cholesterol accumulation in these mice. These results show that the PI3K/Akt/FoxO1 pathway contributes to the regulation of ABCA1 expression in response to IGF1 stimulation that suppressed FL in GH-deficient mice. |
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| 言語 | en | |||||||||||||
| 学位名 | ||||||||||||||
| 言語 | ja | |||||||||||||
| 学位名 | 博士（医学） | |||||||||||||
| 学位授与機関 | ||||||||||||||
| 識別子Scheme | kakenhi | |||||||||||||
| 識別子 | 16201 | |||||||||||||
| 言語 | ja | |||||||||||||
| 機関名 | 香川大学 | |||||||||||||
| 言語 | en | |||||||||||||
| 機関名 | Kagawa University | |||||||||||||
| 学位授与年月日 | ||||||||||||||
| 学位授与年月日 | 2018-12-26 | |||||||||||||
| 学位授与番号 | ||||||||||||||
| 学位授与番号 | 甲第701号 | |||||||||||||
| 権利 | ||||||||||||||
| 言語 | en | |||||||||||||
| 権利情報 | Copyright © 2018 the American Physiological Society | |||||||||||||
| 論文ID（NAID） | ||||||||||||||
| 識別子タイプ | NAID | |||||||||||||
| 関連識別子 | 500001323388 | |||||||||||||
| PubMed番号 | ||||||||||||||
| 識別子タイプ | PMID | |||||||||||||
| 関連識別子 | 30130150 | |||||||||||||
| 関連サイト | ||||||||||||||
| 関連タイプ | isVersionOf | |||||||||||||
| 識別子タイプ | DOI | |||||||||||||
| 関連識別子 | https://doi.org/10.1152/ajpendo.00134.2018 | |||||||||||||
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| 関連タイプ | isIdenticalTo | |||||||||||||
| 識別子タイプ | URI | |||||||||||||
| 関連識別子 | https://dl.ndl.go.jp/pid/11246015 | |||||||||||||
| 著者版フラグ | ||||||||||||||
| 出版タイプ | P | |||||||||||||
| 出版タイプResource | http://purl.org/coar/version/c_fa2ee174bc00049f | |||||||||||||
| キーワード | ||||||||||||||
| 言語 | en | |||||||||||||
| 主題Scheme | Other | |||||||||||||
| 主題 | ABCA1 | |||||||||||||
| キーワード | ||||||||||||||
| 言語 | en | |||||||||||||
| 主題Scheme | Other | |||||||||||||
| 主題 | IGF1 | |||||||||||||
| キーワード | ||||||||||||||
| 言語 | en | |||||||||||||
| 主題Scheme | Other | |||||||||||||
| 主題 | adult growth hormone deficiency | |||||||||||||
| キーワード | ||||||||||||||
| 言語 | en | |||||||||||||
| 主題Scheme | Other | |||||||||||||
| 主題 | fatty liver | |||||||||||||
| KEID | ||||||||||||||
| 28572 | ||||||||||||||
