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

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. 2007Res. . 48: 2020Res. -2027. We investigated the mechanism for FGF-1 to upregulate apoE transcription. FGF-1 increased apoE and liver X receptor a (LXRa) mRNAs in rat astrocytes. Increase of LXRa 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 LXRa, 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 2450 and 2320 bp, and the direct repeat 4 (DR4) element in this region (2448 to 2433 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 LXRa being mediated by both LXRa expression and an LXRa ligand biosynthesis. Apolipoprotein E (apoE) is a glycoprotein composed of 299 amino acids and plays critical roles in lipid metabolism. While most of apolipoproteins are synthesized and secreted primarily by the liver and intestine, apoE is in addition secreted by other cells outside the enterohepatic axis, such as macrophages and adipocytes (1, 2). ApoE is also synthesized by astrocytes and microglia in the central nervous system (CNS) and forms HDL as a major lipoprotein in CNS (3, 4). CNS is segregated from systemic circulation by the blood brain barrier and prevented from access to plasma lipoproteins, so that HDL generated in CNS is the exclusive lipid transport system among the CNS cells (5). ApoE-HDL plays many...

Epigenetic regulation of oxysterol formation

“…Treatment of SH-SY5Y cells with inhibitors of mitogen activated kinase-kinase (MEK) or extracellular signal-regulated kinase-1 (ERK) potentiated the stimulatory effect of the HDAC inhibitor trichostatin A (TSA). This is in line with data on Cyp46a1 mRNA levels presented by Lu et al, in a rat astrocyte model, indicating increased mRNA levels following MEK inhibition, although there is high variability in these results [36]. In contrast treatment with the protein phosphatase inhibitor okadaic acid reduced the potency of the TSA effect.…”

A variant within FGF1 is associated with Alzheimer's disease in the Han Chinese population

“…Previous study reported that FGF1 could regulate biogenesis of APOE and HDL [Lu et al, 2009]. We were not able to determine the associations among the rs34011 variation and other clinical variables such as lipid levels because of the limited access to patients' data.…”

“…FGF1 can affect the neuron survival in vulnerable brain areas [Thorns et al, 2001] and the level of FGF1 in CSF and serum was increased in AD patients [Mashayekhi et al, 2010]. In cultured rat astrocytes, FGF1 can regulate biogenesis of APOE and HDL which were highly associated with AD [Ito et al, 2007;Lu et al, 2009] and also can induce ATP release [Garre et al, 2010]. Due to the important role in the central nervous system, FGF1 has been reported to be associated with schizophrenia and intracranial aneurysm.…”

“…Both genes have multifunction in a variety of biological processes in neuron system including regulating neuron survival activities. FGF1 can affect the neuron survival in vulnerable brain areas in AD patients and also can up-regulate biogenesis of APOE and high density of lipoprotein (HDL) in murine astrocytes [Guo and Mattson, 2000;Lu et al, 2009]. P73, a paralogue of the P53 tumor suppressor, could protect the murine neurons from the toxicity of tau hyperphosphorylation during aging and degeneration [Cancino et al, 2013].…”

Cadmium down-regulates apolipoprotein E (ApoE) expression during malignant transformation of rat liver cells: direct evidence for DNA hypermethylation in the promoter region of ApoE

“…There are hints that this effect of Cd may occur through epigenetic means. In this regard, we have observed that: 1) suppressed expression of ApoE by Cd is re-activated by 5-aza-2'-deoxycytidine (5-aza-dC), an effective DNA demethylating agent; and 2) possible involvement of liver X receptor α (LXRα, NR1H3) as a positive transcriptional factor (Laffitte et al, 2001;Lu et al, 2009). However, details of the molecular mechanisms precise events, such as a direct evidence for the Cd-induced DNA methylation, have not been resolved.…”