ABCA7 expression is regulated by cellular cholesterol through the SREBP2 pathway and associated with phagocytosis

Iwamoto, Noriyuki; Abe-Dohmae, Sumiko; Sato, Ryuichiro; Yokoyama, Shinji

doi:10.1194/jlr.m600127-jlr200

Cited by 98 publications

(125 citation statements)

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“…and overexpressed (13). However, endogenously expressed ABCA7 is not expressed on the cell surface and may not be involved in HDL biogenesis (20,26). This view supports the finding that SAA does not produce HDL with the cells of ABCA1-KO mice, in which ABCA7 expression is increased (20).…”

Section: Discussionsupporting

confidence: 77%

“…However, endogenously expressed ABCA7 is not expressed on the cell surface and may not be involved in HDL biogenesis (20,26). This view supports the finding that SAA does not produce HDL with the cells of ABCA1-KO mice, in which ABCA7 expression is increased (20). Therefore, there is unlikely to be an alternative pathway(s) for SAA-HDL production to the ABCA1-dependent mechanism, at least in vivo.…”

Section: Discussionsupporting

confidence: 74%

“…Primers used for quantitative RT-PCR were as follows: for SAA, 5 ¶-AGA TGC TCT CTG GGG AAA CA-3 ¶ (forward) and 5 ¶-TAC CCT CTC CTC CTC AAG CA-3 ¶ (reverse); for ABCG1, 5 ¶-TCC ATC GTC TGT ACC ATC CA-3 ¶ (forward) and 5 ¶-TTC AGA CCC AGA TCC CTC AG-3 ¶ (reverse); for apoA-I, 5 ¶-ACG TAT GGC AGC AAG ATG AAC-3 ¶ (forward) and 5 ¶-AGA GCT CCA CAT CCT CTT TCC-3 ¶ (reverse). Primers for 18S rRNA and ABCA1 were prepared as described previously (20). Results were normalized to 18S rRNA.…”

Section: Rt-pcrmentioning

confidence: 99%

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Biogenesis of HDL by SAA is dependent on ABCA1 in the liver in vivo

Abe-Dohmae

Tsujita

et al. 2008

Journal of Lipid Research

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Serum amyloid A (SAA) was markedly increased in the plasma and in the liver upon acute inflammation induced by intraperitoneal injection of lipopolysaccharide (LPS) in mice, and SAA in the plasma was exclusively associated with HDL. In contrast, no HDL was present in the plasma and only a small amount of SAA was found in the VLDL/LDL fraction (d , 1.063 g/ml) after the induction of inflammation in ABCA1-knockout (KO) mice, although SAA increased in the liver. Primary hepatocytes isolated from LPS-treated wild-type (WT) and ABCA1-KO mice both secreted SAA into the medium. SAA secreted from WT hepatocytes was associated with HDL, whereas SAA from ABCA1-KO hepatocytes was recovered in the fraction that was .1.21 g/ml. The behavior of apolipoprotein A-I (apoA-I) was the same as that of SAA in HDL biogenesis by WT and ABCA1-KO mouse hepatocytes. Lipid-free SAA and apoA-I both stabilized ABCA1 and caused cellular lipid release in WT mouse-derived fibroblasts, but not in ABCA1-KO mousederived fibroblasts, in vitro when added exogenously. We conclude that both SAA and apoA-I generate HDL largely in hepatocytes only in the presence of ABCA1, likely being secreted in a lipid-free form to interact with cellular ABCA1. In the absence of ABCA1, nonlipidated SAA is seemingly removed rapidly from the extracellular space.-Hu, W., S. Abe-Dohmae, M. Tsujita, N. Iwamoto, O. Ogikubo, T. Otsuka, Y. Kumon, and S. Yokoyama. Biogenesis of HDL by SAA is dependent on ABCA1 in the liver in vivo. J. Lipid Res. 2008. 49: 386-393.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionsupporting

confidence: 74%

Section: Rt-pcrmentioning

confidence: 99%

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Biogenesis of HDL by SAA is dependent on ABCA1 in the liver in vivo

Abe-Dohmae

Tsujita

et al. 2008

Journal of Lipid Research

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“…To obtain a reporter construct with mutation of apoE DR4 element (DR4mu), site-directed mutagenesis was performed to introduce the DR4 at 2448 to 2433 bp of the 2690 to 19 reporter gene using a Quick Change II Site-Directed Mutagenesis Kit (Stratagene, La Jolla, CA) and the respective primers, DR4 of forward: 5′-CCGGGGATGGGGAGttaaCACCGTGGCAGAGGAATCACTA-3′, reverse: 5′-TAGTGATTCCTCTGCCACGGTGttaaCTCCC-CATCCCCGG-3′ (lowercase letters indicate mutated nucleotides). The plasmid for expression of LXRa and the reporter plasmid containing four tandem repeats of LXREs upstream of the thymidine kinase (TK) promoter and its mutant, LXRE-TK and LXREmut-TK, the promoter plasmid containing sterol regulatory element (SRE), were prepared as previously described (19,20). 3T3 cells were grown to 60-70% confluence in 24-well plates, transfected with 1 mg of plasmid DNA including 0.2 mg LXRa expression vector, 0.77 mg reporter gene construct, and 30 ng hRluc-TK (Promega; for normalization) using Lipofectamine 2000 (Invitrogen).…”

Section: Construction Of Luciferase Reporter Genes and Luciferaase Assaymentioning

confidence: 99%

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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“…Recent demographic studies have shown a decrease in incidences in developed countries most likely due to improved treatment and prevention of vascular risk factors 2, 3, 4. Genome‐wide association studies (GWAS) have revealed novel molecular pathways, among these the ATP‐binding‐cassette transporter A7 ( ABCA7 ),5, 6 which may be involved in both transmembrane lipid transport and phagocytosis of amyloid‐ β in the brain 7, 8, 9, 10, 11, 12, 13, 14. Following these GWAS findings, rare loss‐of‐function variants in ABCA7 were reported to confer risk of Alzheimer's disease in case–control studies in Icelandic and Belgian populations 15, 16.…”

Section: Introductionmentioning

confidence: 99%

ABCA7 and risk of dementia and vascular disease in the Danish population

Kjeldsen

Tybjærg‐Hansen

Nordestgaard

et al. 2017

Ann Clin Transl Neurol

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Objective ATP‐binding‐cassette transporter A7(ABCA7) is suggested to be involved in lipid transport as well as in phagocytosis of amyloid‐β in the brain. We tested the hypothesis that a common genetic variant in ABCA7 is associated with dementia, ischemic heart disease, ischemic cerebrovascular disease, and with lipid levels in the general population, independent of the common apolipoprotein E(APOE) genotype.MethodsFor this purpose, we genotyped a common genetic variant in ABCA7, identified in genome‐wide‐association‐studies of Alzheimer's disease, in 104,258 individuals from the Danish general population, and also meta‐analyzed our results with publicly available consortia data.ResultsMultifactorially adjusted hazard ratios for Alzheimer's disease were 1.07 (95% confidence interval:0.93–1.23) and 1.72 (1.24–2.40) for GA and AA versus GG genotype. Results were similar after APOE genotype adjustment and when only APOE ɛ33 carriers were studied. Including 178,304 individuals, the meta‐analyzed odds ratio for Alzheimer's disease per one allele ABCA7 rs4147929 increase was 1.15 (1.12–1.18). ABCA7 genotype was not convincingly associated with vascular dementia, ischemic heart disease, ischemic cerebrovascular disease, or with lipid levels. Including 288,563 individuals, meta‐analyzed odds ratios for ischemic heart disease per one allele ABCA7 rs4147929 increase was 1.01 (0.99–1.03).InterpretationA common genetic variant in ABCA7 was associated with high risk of Alzheimer's disease independent of APOE genotype. The lack of association with vascular dementia, ischemic heart disease, ischemic cerebrovascular disease, and with lipid levels suggests that ABCA7 is not important for atherosclerosis. Thus, our findings support the suggested role of ABCA7 in Alzheimer's disease pathology and phagocytic clearance of amyloid‐β in the brain.

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ABCA7 expression is regulated by cellular cholesterol through the SREBP2 pathway and associated with phagocytosis

Cited by 98 publications

References 44 publications

Biogenesis of HDL by SAA is dependent on ABCA1 in the liver in vivo

Biogenesis of HDL by SAA is dependent on ABCA1 in the liver in vivo

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

ABCA7 and risk of dementia and vascular disease in the Danish population

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