Mechanism for FGF-1 to regulate biogenesis of apolipoprotein E-high density lipoprotein in astrocytes

JIn-ichi Ito, Yuko Nagayasu, Kuniko Okumura-Noji, Rui Lu, Tomo Nishida, Yutaka Miura, Kiyofumi Asai, Alireza Kheirollah, Seiichi Nakaya, and Shinji Yokoyama

Biochemistry, Cell Biology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601

Corresponding Author: syokoyam{at}med.nagoya-cu.ac.jp

Fibroblast growth factor-1 (FGF-1) is synthesized and secreted by astrocytes and stimulates biogenesis of apolipoprotein (apo) E-high density lipoprotein (HDL) by an autocrine mechanism in astrocytes (Biochim. Biophys. Acta 1589, 261-272, 2002 and J. Lipid Res. 46, 679-686, 2005). This reaction plays a crucial role in the recovery mechanism of brain injury (Neurochem. Int. 45, 23-30, 2004). We investigated mechanism for FGF-1 to stimulate apoE-HDL biogenesis in astrocytes focusing on signaling pathways. FGF-1 stimulated cholesterol biosynthesis without enhancing its release in apoE-deficient mouse astrocytes, indicating a signaling pathway independent of apoE biosynthesis up-regulation. SU5402, an inhibitor of the FGF-1 receptor, inhibited the FGF-1-induced phosphorylation of MEK, ERK, and Akt, as well as stimulation of all the apoE-HDL biogenesis-related events in rat astrocytes. LY294002, an inhibitor of phosphatidylinositide 3-OH kinase (PI3K) and therefore of Akt phosphorylation, inhibited secretion of apoE-HDL but did not influence cholesterol biosynthesis, while U0126, an inhibitor of MEK and consequently of ERK phosphorylation, inhibited cholesterol biosynthesis but not apoE-HDL secretion. Increase of apoE-mRNA by FGF-1 was uninfluenced by either inhibitor. When rat apoE/pcDNA3.his was transfected to the transformed rat astrocyte cells GA-1 that otherwise do not synthesize apoE (GA-1/25), apoE-mRNA level was not influenced but its secretion was increased by FGF-1 as phosphorylation of Akt was induced. This increase by FGF-1 was suppressed by LY294002. Lipid biosynthesis was also increased by FGF-1 in GA-1/25 and suppressed by U0126. We thus concluded that FGF-1 upregulates apoE-HDL biogenesis by using at least three independent signaling pathways. The PI3K/Akt pathway upregulates secretion of apoE/apoE-HDL, the MEK/ERK pathway stimulates cholesterol and other lipid biosynthesis, and an unknown pathway enhances apoE transcription.

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