Oleic Acid Modulates the Post-translational Glycosylation of Macrophage ApoE to Increase Its Secretion

Huang, Zhenjun; Gu, De Sheng; Mazzone, Theodore

doi:10.1074/jbc.m402631200

Cited by 25 publications

(19 citation statements)

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“…On the other hand, intracellular retention of apoE in some other cell types, for example neurons, may positively correlate to cellular functions including neurite outgrowth and stabilization of the cytoskeleton (37) and therefore may be more desirable than efficient secretion. Macrophage apoE secretion is regulated by multiple mechanisms, including post-transcriptional glycosylation (38), intracellular sterol milieu (39), cholesterol loading (40,41), cell surface receptor expression (42)(43)(44), and presence of apoAI/ HDL in the culture medium (45). Whether the secretory block of apoE2 affects cholesterol homeostasis or other aspects of macrophage biology (i.e.…”

Section: Discussionmentioning

confidence: 99%

Impaired Secretion of Apolipoprotein E2 from Macrophages

Fan

Qiu

Overton

et al. 2007

Journal of Biological Chemistry

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Human apoE is a multifunctional and polymorphic protein synthesized and secreted by liver, brain, and tissue macrophages. Here we show that apoE isoforms and mutants expressed through lentiviral transduction display cell-specific differences in secretion efficiency. Whereas apoE3, apoE4, and a natural mutant of apoE4 (apoE-Cys 142 ) were efficiently secreted from macrophages, apoE2 and a non-natural apoE mutant (apoE-Cys 112 /Cys 142 ) were retained in the perinuclear region and only minimally secreted. The secretory block for apoE2 in macrophages was not affected by the ablation of LDLR (low density lipoprotein receptor), ABCA-1, or SR-BI (scavenger receptor class B type I) but was released in the absence of low density lipoprotein receptorrelated protein (LRP). In co-immunoprecipitation experiments, an anti-apoE antibody pulled down two times more LRP in apoE2-transduced macrophages than in apoE3-expressing macrophages. Non-reducing SDS-PAGE/Western blot analyses showed that macrophage apoE2 is mostly dimeric and multimeric, whereas apoE3 is predominantly monomeric. ApoE2 retention and multimer formation also occurred in human macrophages derived from the monocyte cell line THP-1. These results were specific for macrophages, as in transduced mouse primary hepatocytes: 1) ApoE2 was secreted as efficiently as apoE3 and apoE4; 2) all isoforms were exclusively in monomeric form; 3) there was no co-immunoprecipitation of apoE and LRP. A microsomal triglyceride transfer protein (MTP) inhibitor nearly deleted apoB100 secretion from hepatocytes without affecting apoE secretion. These data show that macrophages retain apoE2, a highly expressed protein carried by about 8% of the human population. Given the role of locally produced apoE in regulating cholesterol efflux, modulating inflammation, and controlling oxidative stress, this unique property of apoE2 may have important impacts on atherogenesis.ApoE, 2 a 299-residue exchangeable plasma apolipoprotein, is a major player in lipoprotein metabolism and cardiovascular disease (1). It also plays critical roles in many other important biological processes, including Alzheimer disease and cognitive function, immunoregulation and response to infectious agents, intracellular cholesterol trafficking and control of oxidation, and apoptosis (2). ApoE is synthesized and secreted primarily by the liver but also by brain, skin, and tissue macrophages throughout the body (1, 3). Although most lipoprotein-associated apoE is of hepatic origin, macrophage apoE is a major regulator of cholesterol entry and exit within the atherosclerotic plaque. The atheroprotective role of macrophage apoE has been well documented. Macrophage-derived apoE has been shown to protect against atherosclerosis, both early (4 -6) and late during plaque development (7,8), and even when expressed in amounts too low to affect plasma lipid levels (9). Moreover, C57BL/6 mice reconstituted with apoE Ϫ/Ϫ bone marrow develop 10-fold more atherosclerosis than control mice fed a butter fat diet without any differences ...

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Section: Discussionmentioning

confidence: 99%

Impaired Secretion of Apolipoprotein E2 from Macrophages

Fan

Qiu

Overton

et al. 2007

Journal of Biological Chemistry

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“…Retained apoE was measured as labeled apoE in cell lysates after a 60 min chase incubation. ApoE degradation was calculated by subtracting secreted and retained apoE (at 60 min chase) from total synthesized cellular apoE present at the start of the chase incubation ( 34,35 ).…”

Section: Analysis Of Adipocyte Apoe Synthesis and Turnovermentioning

confidence: 99%

“…Biosynthetically labeled apoE in the cell and medium was measured as previously described ( 34,35 ). Briefl y, cell lysates and culture medium were immunoprecipitated with a goat antihuman apoE antibody.…”

Section: Analysis Of Adipocyte Apoe Synthesis and Turnovermentioning

confidence: 99%

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Expression of the human apoE2 isoform in adipocytes: altered cellular processing and impaired adipocyte lipogenesis

Huang

Maeda

Mazzone

2011

Journal of Lipid Research

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which adipose tissue infl uences organismal substrate distribution and metabolism in both physiological and pathophysiological states. Recently, the unexpected observation was made that the endogenous expression of apoE in adipose tissue and adipocytes importantly infl uences adipocyte differentiated function. Adipocytes that do not express endogenous apoE are smaller, contain less lipid, display a defect in lipogenesis and substrate acquisition from extracellular lipoproteins, and have alterations in the expression of genes controlling adipocyte lipid turnover ( 4-7 ). Moreover, these defects cannot be corrected by the provision of extracellular apoE in vitro or in vivo, but can be corrected by adenoviral-mediated expression of endogenous apoE in adipocytes ( 4, 5 ). Because of these effects on adipose tissue metabolism, endogenous adipocyte apoE also importantly infl uences the systemic distribution of substrate in intact animals ( 5 ). A physiological role for endogenous adipocyte apoE expression in the regulation of organismal metabolism is further underscored by the recent demonstration of physiologically relevant pathways for regulating adipocyte apoE expression (8)(9)(10)(11)(12)(13)(14).In humans, apoE is a polymorphic protein, and three common isoforms have been identifi ed: apoE2 (Cys ). The apoE3 isoform is by far the most common and is present in more than 75% of individuals. The presence of the apoE2 or apoE4 isoform has been associated with important human diseases and alterations in systemic lipoprotein metabolism ( 15-17 ). There are also observations in human populations suggesting a relationship between apoE isoform expression and adiposity, and a relationship between adiposity and lipid metabolism ( 18,19 ). In addition, important differences in cellular turnover of the apoE isoforms, with related implications for differentiated Abstract Expression of apoE in adipocytes has been shown to have an important role in modulating adipocyte triglyceride (TG) metabolism and gene expression that is independent of circulating and extracellular apoE. The impact of adipocyte expression of common human apoE isoforms was evaluated using adipocytes harvested from human apoE2, -3, and -4 knock-in mice. Expression of the apoE2 isoform was associated with an increase in adipocyte apoE gene expression and apoE synthesis. Newly synthesized apoE2 was unstable in adipocytes and demonstrated increased degradation and decreased secretion. ApoE2-expressing mice were hyperlipidemic, and had increased size of gonadal fat pads and of adipocytes, compared with apoE3 mice. In isolated cells, however, expression of the apoE2 isoform produced defective lipogenesis and increased TG hydrolysis. Incubation of adipose tissue with apoE3-containing TG-rich lipoproteins resulted in a signifi cant increase in TG in adipose tissue from apoE3 and -E4 mice, but not apoE2 mice. Reduced capacity to internalize FFA as lipogenic substrate contributed to defective lipogenesis. Newly synthesized apoE2 is unstable in adipocytes and results in...

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“…24,27 This is supported by other studies showing that oleic acid stimulates secretion of macrophage apoE while apparently reducing its sialylation. 28 The possibility that glycosylation and sialylation may affect recycling of secreted apoE (see below) remains unexplored. …”

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confidence: 99%

Regulation of Endogenous Apolipoprotein E Secretion by Macrophages

Kockx

Jessup

Kritharides

2008

ATVB

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Abstract-Apolipoprotein E has critical roles in the protection against atherosclerosis and is understood to follow the classical constitutive secretion pathway. Recent studies have indicated that the secretion of apoE from macrophages is a regulated process of unexpected complexity. Cholesterol acceptors such as apolipoprotein A-I, high density lipoprotein, and phospholipid vesicles can stimulate apoE secretion. The ATP binding cassette transporter ABCA1 is involved in basal apoE secretion and in lipidating apoE-containing particles secreted by macrophages. However, the stimulation of apoE secretion by apoA-I is ABCA1-independent, indicating the existence of both ABCA1-dependent and -independent pathways of apoE secretion. The release of apoE under basal conditions is also regulated, requiring intact protein kinase A activity, intracellular calcium, and an intact microtubular network. Mathematical modeling of apoE turnover indicates that whereas some pools of apoE are committed to either secretion or degradation, other pools can be diverted from degradation toward secretion. Targeted inhibition or stimulation of specific apoE trafficking pathways will provide unique opportunities to regulate the biology of this important molecule. Key Words: lipid and lipoprotein metabolism Ⅲ atherosclerosis pathophysiology Ⅲ mechanisms of atherosclerosis Ⅲ cell biology/structural biology Ⅲ cell signalling/signal transduction A polipoprotein E (apoE) is a 34-kDa protein that is produced and secreted by many cell types such as hepatocytes, smooth muscle cells, neuronal cells, and macrophages. As a constituent of plasma lipopoproteins, apoE directs movement of lipids from the periphery to the liver, where high affinity binding of apoE to the LDL receptor and other members of the LDL-receptor family facilitates uptake of the lipoprotein particles. A critical role for apoE in the protection against atherosclerosis was clearly established by the development of the apoE knockout mouse and subsequent studies which showed that macrophage-specific expression of apoE was antiatherogenic. 1,2 The mechanisms by which macrophage apoE is antiatherogenic may include stimulating the removal of excess cholesterol from macrophage foam cells, 3 as well as anti-inflammatory, 4 antiproliferative, 5 and immunomodulatory properties. 6,7 The regulation of the secretion of apoE from macrophages is thus of great importance to our understanding of the atherosclerotic process.The aim of this review is to describe the regulation of the secretion of apoE by macrophages, in light of recent observations indicating that its trafficking and secretion are under the control of signaling pathways. Although recycling of lipoprotein-derived apoE is referenced briefly for comparison, a detailed analysis of apoE recycling is beyond the scope of the present review and the interested reader is directed to recent excellent reviews on this topic. 8 -10 Basic Biology of ApoE in Macrophages Transcriptional Regulation of ApoE SynthesisTranscription of macrophage apoE can ...

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Oleic Acid Modulates the Post-translational Glycosylation of Macrophage ApoE to Increase Its Secretion

Cited by 25 publications

References 47 publications

Impaired Secretion of Apolipoprotein E2 from Macrophages

Impaired Secretion of Apolipoprotein E2 from Macrophages

Expression of the human apoE2 isoform in adipocytes: altered cellular processing and impaired adipocyte lipogenesis

Regulation of Endogenous Apolipoprotein E Secretion by Macrophages

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