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PMID:19229075

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Citation

Lu, R, Ito, J, Iwamoto, N, Nishimaki-Mogami, T and Yokoyama, S (2009) FGF-1 induces expression of LXRalpha and production of 25-hydroxycholesterol to upregulate the apoE gene in rat astrocytes. J. Lipid Res. 50:1156-64

Abstract

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.

Links

PubMed PMC2681397 Online version:10.1194/jlr.M800594-JLR200

Keywords

Animals; Apolipoproteins E/genetics; Astrocytes/drug effects; Astrocytes/metabolism; Base Sequence; Butadienes/pharmacology; Cells, Cultured; DNA Primers/genetics; DNA-Binding Proteins/genetics; Fibroblast Growth Factor 1/pharmacology; Gene Expression/drug effects; Hydroxycholesterols/metabolism; MAP Kinase Signaling System/drug effects; Models, Biological; Nitriles/pharmacology; Orphan Nuclear Receptors; Promoter Regions, Genetic; RNA, Messenger/genetics; RNA, Messenger/metabolism; Rats; Receptors, Cytoplasmic and Nuclear/genetics; Recombinant Proteins/pharmacology; Up-Regulation/drug effects

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:FGFR1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR1H3

enables

GO:0000976: transcription cis-regulatory region binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:NR1H3

GO:0031490: chromatin DNA binding

ECO:0000314:

F

Figure 5: Chip assay shows that LXRα binds to the apoE promoter

complete

RAT:NR1H3

GO:0010552: positive regulation of gene-specific transcription from RNA polymerase II promoter

ECO:0000315:

P

Figure 2A and 2b: Inhibition of LXRα by using siRNA (in Fig 2A) or by using arachidonic acid (in Fig 2B) resulted in a decrease in cellular apoE protein, despite the presence of FGF-1, suggesting that LXRα regulates apoE gene transcription. Figure 3: suggests that the upregulation of the apoE gene transcription in astrocytes is associated with the increase of LXRα, both being regulated by cellular sterol biosynthesis, as when the cells were treated with compactin, an inhibitor of HMG-CoA reductase (involved in the control of cholesterol biosynthesis), the FGF-1 induced increase of LXRα and apoE mRNA were decreased.

complete

RAT:NR1H3

GO:0009306: protein secretion

ECO:0000315:

P

Figure 2A and 2b: Inhibition of LXRα by using siRNA (in Fig 2A) or by using arachidonic acid (in Fig 2B) resulted in a decrease in secreted apoE protein, despite the presence of FGF-1, suggesting that LXRα plays a role in apoE secretion.

NOTE: a more specific term could be used if it was available “apolipoprotein secretion”

complete

HUMAN:FGF1

GO:0010552: positive regulation of gene-specific transcription from RNA polymerase II promoter

ECO:0000314:

P

Figure 1A: FGF-1 increases the expression of LXRα mRNA Figure 1A: FGF-1 increases the expression of apoE mRNA Figure 1B: FGF-1 increases the expression of ABCA1 mRNA Figure 4B: the luciferase assay shows that FGF-1 activates the apoE gene. Also figure 4C shows that responses of the reporter gene to FGF-1 disappear when a mutation is introduced on the promoter sequence Figure 5: Chip assay demonstrated that FGF-1 activates LXR to enhance expression of the apoE gene through its interaction with the LXRE of the endogenous apoE promoter

NOTE: From the company's website the only recombinant FGF-1 protein they have at the moment is human, so I’m assuming it is human based on the current Sigma-Aldrich catalogue.

complete

HUMAN:FGF1

GO:0045542: positive regulation of cholesterol biosynthetic process

ECO:0000314:

P

Figure 6A: this shows that cholesterol biosynthesis is increased by FGF-1 Figure 6D: this shows an increase of cholesterol 25-hydroxylase mRNA by FGF-1 Figure 6F: this shows an increase of 25-hydroxycholesterol (a ligand of LXR) by FGF-1 Figure 6B: this shows that IGF-1 increases the expression of HMG-CoA reductase gene

NOTE 1: From the company's website the only recombinant FGF-1 protein they have at the moment is human, so I’m assuming it is human based on the current Sigma-Aldrich catalogue.

NOTE 2: a more specific term could be used if it was available "regulation of cellular cholesterol metabolic process by positive regulation of transcription from an RNA polymerase II promoter"

complete

HUMAN:FGF1

GO:0009306: protein secretion

ECO:0000314:

P

Figure 2 and 3: The presence of FGF-1 resulted in an increase in the levels of secreted apoE protein

NOTE 1: From the company's website the only recombinant FGF-1 protein they have at the moment is human, so I’m assuming it is human based on the current Sigma-Aldrich catalogue.

NOTE 2: a more specific term could be used if it was available “apolipoprotein secretion”

complete

HUMAN:FGF1

involved_in

GO:1902533: positive regulation of intracellular signal transduction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FGF1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FGF1

involved_in

GO:0045542: positive regulation of cholesterol biosynthetic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR1H3

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR1H3

enables

GO:0044212: transcription regulatory region DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:FGFR1

GO:0010552: positive regulation of gene-specific transcription from RNA polymerase II promoter

ECO:0000315:

P

Figure 1C: an FGFR1 inhibitor (PD173074) suppresses expression of LXRα and apoE mRNA, suggesting that FGFR1 plays a role in the expression of LXRα and apoE Figure 7A: this shows that effect of FGF-1 expression was abolished by inhibition of FGFR1 using inhibitor PD173074

complete

HUMAN:MK01

GO:0045941: positive regulation of transcription

ECO:0000315:

P

Figure 1C: an MEK/ERK pathway inhibitor (U1026) partially suppresses expression of LXRα and apoE mRNA, suggesting that MEK/ERK plays a role in the expression of LXRα and apoE Figure 7A: this shows that effect of FGF-1 expression was partially suppressed by inhibition of the MEK/ERK pathway (using inhibitor U1026), thus the MEK/ERK plays a role in the expression of FGF-1

complete


See also

References

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