FGF-1 induces expression of LXRalpha and production of 25-hydroxycholesterol to upregulate the apoE gene in rat astrocytes.
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 alpha (LXRalpha) mRNAs in rat astrocytes. Increase of LXRalpha 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 LXRalpha, 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 LXRalpha being mediated by both LXRalpha expression and an LXRalpha ligand biosynthesis.
Lu
Rui
R
Department of Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
Ito
Jinichi
J
Iwamoto
Noriyuki
N
Nishimaki-Mogami
Tomoko
T
Yokoyama
Shinji
S
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D001483:Base Sequence; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006888:Hydroxycholesterols / Q000378:metabolism*; D000071518:Liver X Receptors; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008954:Models, Biological; D009570:Nitriles / Q000494:pharmacology; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D011994:Recombinant Proteins / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D001057:Apolipoproteins E; D002070:Butadienes; D017931:DNA Primers; D004268:DNA-Binding Proteins; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; D009570:Nitriles; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; C113580:U 0126; D016220:Fibroblast Growth Factor 1; C007997:25-hydroxycholesterol