IGF1 suppresses cholesterol accumulation in the liver of growth hormone deficient mice via the activation of ABCA1

( 最大 2000 件 )
URI http://shark.lib.kagawa-u.ac.jp/kuir/metadata/28572
タイトル
IGF1 suppresses cholesterol accumulation in the liver of growth hormone deficient mice via the activation of ABCA1
ファイル
内容記述

Abstract

Recently, several clinical studies have suggested that adult growth hormone deficiency that also has low concentration of IGF1 is associated with an increased prevalence of fatty liver (FL). ABCA1 is a pivotal regulator of lipid efflux from cells to apolipoproteins and play 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 ChIP assay. Cholesterol accumulation was analyzed by Oil-Red-O stain and cholesterol content measurement. We confirmed that IGF1 up-regulated 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 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. In vivo experiments, we used an inhibitor for the GH receptor (Pegvisomant) to reduce the IGF1 level. A HFD induced FL in mice (C57BL/6J) given Pegvisomant-treat. 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.

KEYWORDS:

ABCA1; Adult growth hormone deficiency; Fatty Liver; IGF1

(医博甲701)

著者
著者 福長 健作
著者(ヨミ) フクナガ ケンサク
著者(別表記) Fukunaga Kensaku
掲載誌
American Journal of Physiology-Endocrinology and Metabolism
掲載誌(別表記)
Am J Physiol Endocrinol Metab.
315
6
開始ページ
E1232
終了ページ
E1241
出版者
American Physiological Society
出版年月日
2018-08-21
ISSN
0193-1849
NCID
AA00066467
PMID
30130150
DOI
10.1152/ajpendo.00134.2018
資料タイプ
学位論文
言語
英語
関連情報
出版社版DOIリンク(URL): https://doi.org/10.1152/ajpendo.00134.2018
関連情報URL
https://doi.org/10.1152/ajpendo.00134.2018
博士論文(全文を含む)
学位授与番号
博甲第701号
学位授与年月日
2018-12-26
学位名
博士(医学)
学位授与機関
香川大学
区分
香川大学
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