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Journal of Lipid Research, Vol. 50, 1156-1164, June 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

FGF-1 induces expression of LXR and production of 25-hydroxycholesterol to upregulate the apoE gene in rat astrocytes

Rui Lu^*, Jinichi Ito^*, Noriyuki Iwamoto^*, Tomoko Nishimaki-Mogami and Shinji Yokoyama^1,*

^* Department of Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
Department of Biochemistry and Metabolism, National Institute of Health Sciences, Tokyo 158-8501, Japan

This study was supported by International HDL Award Program, in part by grants-in-aid from The Ministries of Education, Science, Technology, Culture, and Sports, and of Health, Welfare, and Labor of Japan, and by the Program for Promotion of Fundamental Studies in Health Sciences of National Institute of Biomedical Innovation. Rui Lu is supported by Postdoctoral Fellowship for Foreign Researchers from the Japan Society for the Promotion of Science.

Published, JLR Papers in Press, February 19, 2009.

¹ To whom correspondence should be addressed. e-mail: syokoyam{at}med.nagoya-cul.ac.jp

Fibroblast growth factor 1 (FGF-1) enhances apolipoprotein E (apoE) expression and apoE-HDL biogenesis in autocrine fashion in astrocytes (Ito, J., Y. Nagayasu, R. Lu, A. Kheirollah, M. Hayashi, and S. Yokoyama. Astrocytes produce and secrete FGF-1, which promotes the production of apoE-HDL in a manner of autocrine action. J. Lipid Res. 2005. 46: 679–686) associated with healing of brain injury (Tada,T., J-i. Ito, M. Asai, and S. Yokoyama. Fibroblast growth factor 1 is produced prior to apolipoprotein E in the astrocytes after cryo-injury of mouse brain. Neurochem. Int. 2004. 45: 23–30). FGF-1 stimulates mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) to increase cholesterol biosynthesis and phosphatidylinositol 3-OH kinase (PI3K)/Akt to enhance apoE-HDL secretion (Ito, J., Y. Nagayasu, K. Okumura-Noji, R. Lu, T. Nishida, Y. Miura, K. Asai, A. Kheirollah, S. Nakaya, and S. Yokoyama. Mechanism for FGF-1 to regulate biogenesis of apoE-HDL in astrocytes. J. Lipid Res. 2007. 48: 2020–2027). We investigated the mechanism for FGF-1 to upregulate apoE transcription. FGF-1 increased apoE and liver X receptor (LXR) mRNAs in rat astrocytes. Increase of LXR mRNA was suppressed by inhibition of the FGF-1 receptor-1 and MEK/ERK but not by inhibition of PI3K/Akt. The increases of apoE mRNA and apoE-HDL secretion were both inhibited by downregulation or inhibition of LXR, while they were partially suppressed by inhibiting cholesterol biosynthesis. We identified the liver X receptor element responsible for activation of the rat apoE promoter by FGF-1 located between –450 and –320 bp, and the direct repeat 4 (DR4) element in this region (–448 to –433 bp) was responsible for the activation. Chromatin immunoprecipitation analysis supported that FGF-1 enhanced association of LXR with the rat apoE promoter. FGF-1 partially activated the apoE promoter even in the presence of an MEK inhibitor that inhibits the FGF-1-mediated enhancement of cholesterol biosynthesis. On the other hand, FGF-1 induced production of 25-hydroxycholesterol by MEK/ERK as an sterol regulatory element-dependent reaction besides cholesterol biosynthesis. We concluded that FGF-1-induced apoE expression in astrocytes depends on LXR being mediated by both LXR expression and an LXR ligand biosynthesis.

Supplementary key words high density lipoprotein • cholesterol • direct repeat 4

Abbreviations: apoE, apolipoprotein E; ChIP, chromatin immunoprecipitation; CNS, central nervous system; ERK, extracellular signal-regulated kinase; FGF, fibroblast growth factor; FGFR1, FGF receptor 1; LXR, liver X receptor; LXRE, LXR response element; MEK, mitogen-activated protein kinase kinase; ERK, extracellular signal-regulated kinase; PI3K, phosphatidylinositol 3-OH kinase; siRNA, small interfering RNA; SRE, sterol regulatory element; TK, thymidine kinase

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