Mechanism for FGF-1 to regulate biogenesis of apoE-HDL in astrocytes.
Fibroblast growth factor-1 (FGF-1) is secreted by astrocytes and stimulates apolipoprotein E (apoE)-HDL biogenesis by an autocrine mechanism to help in recovery from brain injury. In apoE-deficient mouse astrocytes, FGF-1 stimulated cholesterol biosynthesis without enhancing its release, indicating a signaling pathway independent of apoE biosynthesis upregulation. SU5402, an inhibitor of FGF receptor, inhibited FGF-1-induced phosphorylation of MEK, ERK, and Akt, as well as all the apoE-HDL biogenesis-related events in rat astrocytes. LY294002, an inhibitor of phosphatidylinositide 3-OH kinase (PI3K) and of Akt phosphorylation, inhibited apoE-HDL secretion but not cholesterol biosynthesis, whereas U0126, an inhibitor of MEK and of ERK phosphorylation, inhibited cholesterol biosynthesis but not apoE-HDL secretion. Increase of apoE-mRNA by FGF-1 was not influenced by either inhibitor. When rat apoE/pcDNA3.his was transfected to transformed rat astrocyte GA-1 cells that otherwise do not synthesize apoE (GA-1/25), FGF-1 did not influence apoE-mRNA, but did increase the apoE secretion and Akt phosphorylation that were suppressed by LY294002. Lipid biosynthesis was increased by FGF-1 in GA-1/25 cells and suppressed by U0126. FGF-1 upregulates apoE-HDL biogenesis by three independent signaling pathways. The PI3K/Akt pathway upregulates secretion of apoE/apoE-HDL, the MEK/ERK pathway stimulates cholesterol biosynthesis, and an unknown pathway enhances apoE transcription.
Ito
Jin-Ichi
J
Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
Nagayasu
Yuko
Y
Okumura-Noji
Kuniko
K
Lu
Rui
R
Nishida
Tomo
T
Miura
Yutaka
Y
Asai
Kiyofumi
K
Kheirollah
Alireza
A
Nakaya
Seiichi
S
Yokoyama
Shinji
S
D000818:Animals; D001057:Apolipoproteins E / Q000096:biosynthesis* / Q000172:deficiency / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002070:Butadienes / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D016220:Fibroblast Growth Factor 1 / Q000502:physiology*; D008055:Lipids / Q000096:biosynthesis; D008075:Lipoproteins, HDL / Q000096:biosynthesis*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects
D001057:Apolipoproteins E; D002070:Butadienes; D002867:Chromones; D008055:Lipids; D008075:Lipoproteins, HDL; D009025:Morpholines; D009570:Nitriles; D011758:Pyrroles; D017468:Receptors, Fibroblast Growth Factor; C105686:SU 5402; C113580:U 0126; C025121:apolipoprotein E-rich HDL; D016220:Fibroblast Growth Factor 1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D020930:MAP Kinase Kinase Kinases