Hepatic Expression of Apolipoprotein E Inhibits Progression of Atherosclerosis without Reducing Cholesterol Levels in LDL Receptor-Deficient Mice

Tsukamoto, Kazuhisa; Tangirala, Rajendra K.; Chun, Sam; Usher, David; Puré, Ellen; Rader, Daniel J.

doi:10.1006/mthe.2000.0028

Cited by 42 publications

(38 citation statements)

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“…ApoE is produced by macrophages in diseased arterial wall during its inflammatory reaction, where it helps to carry away cholesterol in locally formed lipoproteins and reduce atherosclerotic plaque 7,8 . This effect can be also mediated by hepatic ApoE, as was proven in mice lacking macrophage-derived ApoE, and is responsible for anti-aterogenic action even without lowering plasma cholesterol levels [9][10][11] . The protein also induce the synthesis of NO in vessel wall 12 and has numerous anti-inflammatory effects 13,14 ApoE is polymorphic, with three isoforms common in general population: E2, E3 and E4.…”

Section: Introductionmentioning

confidence: 82%

Apolipoprotein E polymorphism is associated with both number of diseased vessels and extent of coronary artery disease in Czech patients with CAD

Máchal¹,

Vašků²,

Hlinomaz³

et al. 2012

BIOMED PAP

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Aims. The impact of ApoE polymorphism on angiographic parameters was assessed in patients referred for coronary angiography. Methods. Elective coronary angiography was performed in 671 subjects (525 men, 146 women, mean age 60±10 years) with symptoms of ischemic heart disease. The patients were divided into: no CAD group (smooth coronary vessels, n=83), one-vessel (n=155), two-vessel (n=170) and three-vessel disease (n=196). Patients with stenoses 0-50% were excluded. Within patients with CAD, we evaluated overall extent of CAD measured by the number of stenotic segments according to AHA (1 segment vs. 2-3 vs. ≥4), and the severity of the most serious stenosis (in percent). ApoE genotype was determined using real-time PCR. Results. The frequency of ε2/ε3 genotype (n=56) was lower in the three-vessel disease group compared to one-vessel disease (OR=0.25, P=0.0019), two-vessel disease (OR=0.31, P=0.0114) or no CAD group (OR=0.24, P=0.0057). Frequency of ε2/ε3 decreased with the number of affected segments (1 vs. ≥4: OR=0.35, P=0.0143). The ε3/ε4+ε4/ε4 genotypes (n=123) were more frequent in CAD patients altogether compared with no CAD group (OR=2.30, P=0.019), while no impact of the ε4 allele on angiographic parameters within the CAD patients was detected. In ε2/ε3 carriers with CAD, lower LDL-cholesterol, total cholesterol and lower use of lipid-lowering drugs were observed. Conclusions. The results show predominantly focal form of CAD in patients with ε2/ε3 genotype. Lower LDL-cholesterol and total cholesterol may play the key role, although other contributing factors are discussed.

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Section: Introductionmentioning

confidence: 82%

Apolipoprotein E polymorphism is associated with both number of diseased vessels and extent of coronary artery disease in Czech patients with CAD

Máchal¹,

Vašků²,

Hlinomaz³

et al. 2012

BIOMED PAP

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“…Experimental evidence suggests that hepatocyte-derived apoE and macrophage-derived apoE may be either functionally different or operate at different physiologic thresholds (10,17,18,(53)(54)(55)(56)(57)(58)(59)(60). The difference in their conformation suggested in this study may underlie the functional difference between hepatocyte and macrophage apoE.…”

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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“…Plasma apoE levels ,5% of wild-type levels derived either from macrophages, adrenal gland, or liver is sufficient to reduce atherosclerosis even in the absence of any change in plasma lipid levels (31)(32)(33)(34). This suggests that the production of apoE by macrophages in the atherosclerotic lesion is not obligatory for atheroprotection.…”

Section: Local Influence Of Apoe On Cells Of the Atherosclerotic Lesionmentioning

confidence: 99%

Apoprotein E as a lipid transport and signaling protein in the blood, liver, and artery wall

Getz

Reardon

2009

Journal of Lipid Research

225

155

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Apoprotein E (apoE) is synthesized by a number of tissues including the liver, brain, adipose tissue, and artery wall. The majority of apoE is found in the plasma associated with specific lipoprotein subclasses and is derived primarily from the liver. However the fact that apoE expression is sustained in nonhepatic tissues suggests that the local production must have some unique functional attribute. ApoE is involved in many steps in lipid and lipoprotein homeostasis, for the triglyceride-rich lipoproteins and for HDL. ApoE is also important for lipid homeostasis in the brain, artery wall, and adipose tissue through its synthesis by glial cells, adipocytes, and macrophages. In addition, nonlipid related functions have also been attributed to apoE, including effects on immune response and inflammation, oxidation, and smooth muscle proliferation and migration. Some of these effects have been shown to be dependent upon different domains of the protein, different concentrations, and lipidation state. Thus, this multifunctional protein impacts normal and pathophysiology at multiple levels.-Getz, G. S., and C. A. Reardon. Apoprotein E as a lipid transport and signaling protein in the blood, liver, and ar tery wall.

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Hepatic Expression of Apolipoprotein E Inhibits Progression of Atherosclerosis without Reducing Cholesterol Levels in LDL Receptor-Deficient Mice

Cited by 42 publications

References 50 publications

Apolipoprotein E polymorphism is associated with both number of diseased vessels and extent of coronary artery disease in Czech patients with CAD

Apolipoprotein E polymorphism is associated with both number of diseased vessels and extent of coronary artery disease in Czech patients with CAD

Impaired Secretion of Apolipoprotein E2 from Macrophages

Apoprotein E as a lipid transport and signaling protein in the blood, liver, and artery wall

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