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

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

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

Author
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
Publication Title
American Journal of Physiology-Endocrinology and Metabolism
Volume
315
Issue
6
Start Page
E1232
End Page
E1241
Publisher
American Physiological Society
Published Date
2018-08-21
ISSN
0193-1849
PMID
30130150
DOI
10.1152/ajpendo.00134.2018
Resource Type
Thesis or Dissertation
Language
eng
Relation
出版社版DOIリンク(URL): https://doi.org/10.1152/ajpendo.00134.2018
Resource URL
https://doi.org/10.1152/ajpendo.00134.2018
Text Version
ETD
Grant ID
博甲第701号
Grant Date
2018-12-26
Degree Name
博士(医学)
Grantor
香川大学
Set
香川大学
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