Astrocytes produce and secrete FGF-1, which promotes the production of apoE-HDL in a manner of autocrine action

Ito, Jin‐ichi; Nagayasu, Yuko; Lu, Rui; Kheirollah, Alireza; Hayashi, Michi; Yokoyama, Shinji

doi:10.1194/jlr.m400313-jlr200

Cited by 30 publications

(19 citation statements)

References 63 publications

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“…An MEK/ERK pathway inhibitor, U0126, partially suppressed expression of apoE and LXRa mRNAs. The inhibition beyond the level of control without exogenous FGF-1 may indicate the presence of the basal autocrine activation by endogenous FGF-1 (14). A PI3K/Akt pathway inhibitor LY294002 that inhibits apoE secretion (15) did not influence the expression of either mRNA.…”

Section: Resultsmentioning

confidence: 97%

“…A schematic model for mechanism by FGF-1 to increase production of apoE-HDL in rat astrocytes. The results from the references (14,15) and those of this study are summarized.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, it is important to understand the background molecular mechanism for this reaction to understand the process of the recovery of the brain damage. We discovered that apoE-HDL production is stimulated by FGF-1 in astrocytes by an autocrine mechanism and helps the healing process of the brain cryo-injury (12)(13)(14). FGF-1 was shown to activate the MEK/ ERK signaling pathway to stimulate cholesterol biosynthesis and the PI3K/Ark pathway for enhancement of apoE-HDL secretion (15).…”

Section: Resultsmentioning

confidence: 99%

“…Long-term culture of rat astrocytes induced the increase of apoE synthesis and apoE-HDL production and enhancement of cholesterol biosynthesis, in comparison to the astrocytes prepared by a conventional method of 1-week primary and 1-week secondary culture (13). FGF-1 was highly expressed and released in these long-cultured cells, and their conditioned medium and FGF-1 both stimulated apoE synthesis, production of apoE-HDL, and cholesterol biosynthesis in the conventionally prepared astrocytes (14).…”

mentioning

confidence: 99%

“…Real-time PCR analysis was performed on an ABI PRISM 7700 sequence detection system using target-specific probes. Those for apoE and LXRa were described elsewhere (14,17). For HMG-CoA reductase, SREBP2, cholesterol 24-hydroxylase (CYP46A1), and cholesterol 25-hydroxylase, the probes chosen were 5′-TGCTGCTTTGGCTGTATGTC-3′ and 5′-TGAGCGT-GAACAAGAACCAG-3′, 5′-CCAAGAAGAAGGCAGGTGAC-3′ and 5′-GGACCCGCTCTACTTCAGTG-3′, 5′-GTGACTAT-GGGCGCTGGTAT-3′ and 5′-ATCAGCTGCTCTGCCTTCTC-3′, and 5′-TAGCCTTCTTGGATGTGCTG-3′and 5′-GTGAGTGGAC-CACGGAAAGT-3′, respectively.…”

Section: Rna Isolation and Real-time Pcr Analysismentioning

confidence: 99%

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

Ito

Iwamoto

et al. 2009

Journal of Lipid Research

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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...

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Section: Resultsmentioning

confidence: 97%

“…A schematic model for mechanism by FGF-1 to increase production of apoE-HDL in rat astrocytes. The results from the references (14,15) and those of this study are summarized.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Section: Rna Isolation and Real-time Pcr Analysismentioning

confidence: 99%

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

Ito

Iwamoto

et al. 2009

Journal of Lipid Research

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The central fibroblast growth factor receptor/beta klotho system: Comprehensive mapping in Mus musculus and comparisons to nonhuman primate and human samples using an automated in situ hybridization platform

Hultman

Scarlett

Baquero

et al. 2019

J of Comparative Neurology

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Central activation of fibroblast growth factor (FGF) receptors regulates peripheral glucose homeostasis and reduces food intake in preclinical models of obesity and diabetes. The current work was undertaken to advance our understanding of the receptor expression, as sites of ligand action by FGF19, FGF21, and FGF1 in the mammalian brain remains unresolved. Recent advances in automated RNAscope in situ hybridization and droplet digital PCR (ddPCR) technology allowed us to interrogate central FGFR/beta klotho (Klb) system at the cellular level in the mouse, with relevant comparisons to nonhuman primate and human brain. FGFR1‐3 gene expression was broadly distributed throughout the CNS in Mus musculus, with FGFR1 exhibiting the greatest heterogeneity. FGFR4 expression localized only in the medial habenula and subcommissural organ of mice. Likewise, Klb mRNA was restricted to the suprachiasmatic nucleus (SCh) and select midbrain and hindbrain nuclei. ddPCR in the rodent hypothalamus confirmed that, although expression levels are indeed low for Klb, there is nonetheless a bonafide subpopulation of Klb+ cells in the hypothalamus. In NHP and human midbrain and hindbrain, Klb + cells are quite rare, as is expression of FGFR4. Collectively, these data provide the most robust central map of the FGFR/Klb system to date and highlight central regions that may be of critical importance to assess central ligand effects with pharmacological dosing, such as the putative interactions between the endocrine FGFs and FGFR1/Klb, or FGF19 with FGFR4.

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Roles of insulin and transferrin in neural progenitor survival and proliferation

Erickson

Paucar

Jackson

et al. 2008

J of Neuroscience Research

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Multipotent neural progenitor cells or neural stem cells (NSC) can be propagated in vitro from a variety of sources and have great potential for neural repair. Although it is well known that NSC divide in response to basic fibroblast growth factor (FGF-2) and epidermal growth factor (EGF), cofactors necessary for survival and maintenance of a multipotent potential are still a matter of debate. In the current study, we examined the requirements for NSC proliferation and survival in vitro using the neurosphere culture system. Apotransferrin (TF), along with EGF and FGF-2, was sufficient for the formation of primary neurospheres derived from embryonic rat cortices. The addition of low concentrations of insulin or insulin-like growth factor-1 (IGF-1) enhanced neurosphere size and number and was necessary for continued passaging. Both insulin and IGF-1 acted at low concentrations, suggesting that their effects were mediated by their cognate receptors, both of which were expressed by neurosphere cultures. Sphere-forming progenitors survived for long periods in culture without EGF or FGF-2 when either insulin or IGF-1 was added to the media. Cell cycle analysis determined that surviving progenitors were relatively quiescent during the period without mitogens. Upon the reintroduction of EGF and FGF-2, surviving progenitors gave rise to new spheres that produced largely glial-restricted progeny compared with sister cultures. These data indicate that the neurogenic potential of NSC may be intimately linked to a continuous exposure to mitogens.

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Astrocytes produce and secrete FGF-1, which promotes the production of apoE-HDL in a manner of autocrine action

Cited by 30 publications

References 63 publications

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

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

The central fibroblast growth factor receptor/beta klotho system: Comprehensive mapping in Mus musculus and comparisons to nonhuman primate and human samples using an automated in situ hybridization platform

Roles of insulin and transferrin in neural progenitor survival and proliferation

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