A Secreted Soluble Form of LR11, Specifically Expressed in Intimal Smooth Muscle Cells, Accelerates Formation of Lipid-Laden Macrophages

Ohwaki, Kenji; Bujo, Hideaki; Jiang, Meizi; Yamazaki, Hiroyuki; Schneider, Wolfgang J.; Saitō, Yasushi

doi:10.1161/atvbaha.106.137091

Cited by 50 publications

(33 citation statements)

References 35 publications

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“…For example, it has been shown that SorLA interacts with the amyloid precurcursor protein (38), a protein that is directly associated with development of Alzheimer's disease. SorLA might play a role in the regulation of formation of lipidladen macrophages in atherosclerotic plaques (39). Sortilin is involved in neuronal apoptosis through its interactions with proneurotrophins and p75 NTR (40).…”

Section: Discussionmentioning

confidence: 99%

Endocytosis of Apolipoprotein A-V by Members of the Low Density Lipoprotein Receptor and the Vps10p Domain Receptor Families

Nilsson

Christensen

Raarup

et al. 2008

Journal of Biological Chemistry

104

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Apolipoprotein A-V (apoA-V) is present in low amounts in plasma and has been found to modulate triacylglycerol levels in humans and in animal models. ApoA-V displays affinity for members of the low density lipoprotein receptor (LDL-R) gene family, known as the classical lipoprotein receptors, including LRP1 and SorLA/LR11. In addition to LDL-A binding repeats, the mosaic receptor SorLA/LR11 also possesses a Vps10p domain. Here we show that apoA-V also binds to sortilin, a receptor from the Vsp10p domain gene family that lacks LDL-A repeats. Binding of apoA-V to sortilin was competed by neurotensin, a ligand that binds specifically to the Vps10p domain. To investigate the biological fate of receptor-bound apoA-V, binding experiments were conducted with cultured human embryonic kidney cells transfected with either SorLA/LR11 or sortilin. Compared with nontransfected cells, apoA-V binding to SorLA/ LR11-and sortilin-expressing cells was markedly enhanced. Internalization experiments, live imaging studies, and fluorescence resonance energy transfer analyses demonstrated that labeled apoA-V was rapidly internalized, co-localized with receptors in early endosomes, and followed the receptors through endosomes to the trans-Golgi network. The observed decrease of fluorescence signal intensity as a function of time during live imaging experiments suggested ligand uncoupling in endosomes with subsequent delivery to lysosomes for degradation. This interpretation was supported by experiments with 125 I-labeled apoA-V, demonstrating clear differences in degradation between transfected and nontransfected cells. We conclude that apoA-V binds to receptors possessing LDL-A repeats and Vsp10p domains and that apoA-V is internalized into cells via these receptors. This could be a mechanism by which apoA-V modulates lipoprotein metabolism in vivo.APOA5 is localized in the apolipoprotein APOA4/APOC3/ APOA1 gene cluster on human chromosome 11q23 (1). Transgenic mice expressing human apolipoprotein A-V (apoA-V) have decreased plasma triacylglycerol (TG) 2 levels, whereas APOA5 knock-out mice show increased plasma TG levels. Genetic variation in the human APOA5 locus correlate with changes in plasma lipoprotein levels (2-4), and a common polymorphism in APOA5 is significantly associated with increased risk for the metabolic syndrome (5, 6). Mutations in the APOA5 gene, leading to truncated apoA-V devoid of lipidbinding domains, have been demonstrated to cause severe hyperlipidemia if present in patients in the homozygous state (7).The mechanism whereby apoA-V exerts its effect on plasma TG levels is unknown. Animal studies and in vitro experiments have given rise to two different hypotheses for the function of apoA-V in vivo, inhibition of VLDL-TG production (8) or modulation of lipoprotein lipase (LPL) activity (8 -11). Adenovirusmediated gene transfer of human apoA-V into apoE-deficient mice decreased plasma TG levels as well as total plasma cholesterol levels without affecting LPL activity (12). In vitro experiments support a role fo...

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Section: Discussionmentioning

confidence: 99%

Endocytosis of Apolipoprotein A-V by Members of the Low Density Lipoprotein Receptor and the Vps10p Domain Receptor Families

Nilsson

Christensen

Raarup

et al. 2008

Journal of Biological Chemistry

104

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“…Polyclonal antibodies against uPAR and HIF-1␣ were from R&D Systems and Cell Signaling Technology, respectively. Recombinant LR11 protein lacking the 104 C-terminal amino acids containing the transmembrane region (sLR11) was prepared as described (22).…”

Section: Methodsmentioning

confidence: 99%

“…The mouse stromal cells, OP-9, were provided by Dr. Osawa (Chiba University). For murine cell sorting, BM cells were first stained with biotinylated-anti-Lineage (Lin) (CD5, B220, CD11b, Gr-1, 7-4, Ter-119) followed by incubating with streptavidin microbeads (Miltenyi Biotec Cell Adhesion Assay-Cell adhesion was determined in 96-well plates as described (22). For experiments using vitronectin-coated plates, wells were coated with 10 ng/well vitronectin for 2 h at 37°C.…”

Section: Methodsmentioning

confidence: 99%

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The Soluble Form of LR11 Protein Is a Regulator of Hypoxia-induced, Urokinase-type Plasminogen Activator Receptor (uPAR)-mediated Adhesion of Immature Hematological Cells

Nishii

Nakaseko

Jiang

et al. 2013

Journal of Biological Chemistry

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Background: Serum levels of the soluble LR11 fragment (sLR11) increase in patients with acute leukemia. Results: Hypoxia-induced factor (HIF)-1␣ activation increases LR11 levels, and sLR11 enhances adhesion of HSPCs to BM stromal cells via a uPAR-mediated pathway. Conclusion: sLR11 regulates hypoxia-induced attachment of HSPCs. Significance: sLR11 may stabilize the hematological pool size by controlling HSPC attachment to the BM niche.

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“…19 The protein concentrations were determined using the BCA Protein Assay Reagent (Pierce, Rockford, IL, USA). For immunoblotting, equal amounts of membrane protein, protein extracted from pelleted beads, or concentrated media were separated by 10% SDS-PAGE after heating to 95 1C for 5 min under reducing conditions, and transferred to a nitrocellulose membrane.…”

Section: Western Blot Analysismentioning

confidence: 99%

Macrophages regulate tumor necrosis factor-α expression in adipocytes through the secretion of matrix metalloproteinase-3

et al. 2008

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Objective: Adipocytes accumulated in the visceral area change their function to induce tumor necrosis factor-a (TNF-a) secretion with concomitant matrix metalloproteinase (MMP)-3 induction in mice. This study was performed to clarify the role of macrophages (Mf)-secreted MMP on the functional changes in adipocytes using a culture system. Design: Cultures of 3T3-L1 adipocytes with THP-1 Mf or the Mf-conditioned medium were used to investigate the role of Mf-MMP on the TNF-a gene in 3T3-L1 adipocytes by the addition of MMP inhibitors. For animal experiments, male C57BL/6J mice were rendered insulin resistant by feeding a high-fat diet, and the expression of an Mf marker F4/80, and MMP-3 genes in mesenteric and subcutaneous fat tissue specimens were examined. Results: Mf-conditioned media (Mf-CM) increased the levels of TNF-a mRNA expression in 3T3-L1 adipocytes, and these adipocyte responses were abolished by treatment with GM6001, a broad-spectrum MMP inhibitor, or NNGH (N-isobutyl-N-(4-methoxyphenylsulfonyl)-glycylhydroxamic acid), an MMP-3 inhibitor. The activated form of MMP-3 enhanced glycerol release as well as TNF-a protein secretion from 3T3-L1 adipocytes. The incubation of adipocytes with MMP-3 inhibited insulin-induced glucose uptake in adipocytes. Furthermore, a high-fat intake increased the expression of MMP-3, decreased the insulin-induced glucose uptake of adipocytes and induced expression of F4/80 in mesenteric fat tissue of C57BL/6 mice. Conclusion: Mf may cause a pathological link with surrounding adipocytes through the secretion of MMP-3 followed by TNF-a expression in adipocytes in visceral fat tissue.

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A Secreted Soluble Form of LR11, Specifically Expressed in Intimal Smooth Muscle Cells, Accelerates Formation of Lipid-Laden Macrophages

Cited by 50 publications

References 35 publications

Endocytosis of Apolipoprotein A-V by Members of the Low Density Lipoprotein Receptor and the Vps10p Domain Receptor Families

Endocytosis of Apolipoprotein A-V by Members of the Low Density Lipoprotein Receptor and the Vps10p Domain Receptor Families

The Soluble Form of LR11 Protein Is a Regulator of Hypoxia-induced, Urokinase-type Plasminogen Activator Receptor (uPAR)-mediated Adhesion of Immature Hematological Cells

Macrophages regulate tumor necrosis factor-α expression in adipocytes through the secretion of matrix metalloproteinase-3

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