Increased atherosclerosis in LDL receptor–null mice lacking ACAT1 in macrophages

Fazio, Sergio; Major, Amy S.; Swift, Larry L.; Gleaves, Linda A.; Accad, Michel; Linton, MacRae F.; Farese, Robert V.

doi:10.1172/jci10310

Cited by 224 publications

(197 citation statements)

References 43 publications

(31 reference statements)

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“…Although deletion or inhibition of ACAT should increase cholesterol efflux via increased accumulation of intracellular free cholesterol, we have shown that elimination of ACAT1 from macrophages of LDLR À/À mice increased arterial lesions and reduced the number of arterial macrophages, likely because of accelerated apoptosis. 32 Feng and Tabas 33 have reached similar conclusions by showing that cholesterol loading in macrophages induces accumulation of free cholesterol and provokes 'toxic' effects including accelerated degradation of ABCA1 protein and reduced efflux of cholesterol from the cell.…”

Section: Macrophage Foam Cell Formation and Cholesterol Homeostasismentioning

confidence: 83%

Macrophages, inflammation, and atherosclerosis

2003

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The macrophage plays a diverse array of roles in atherogenesis and lipoprotein metabolism. The macrophage functions as a scavenger cell, an immune mediator cell, and as a source of chemotactic molecules and cytokines. Chemokines have been implicated in promoting migration of monocytes into the arterial intima. Monocyte chemoattractant protein-1 (MCP-1) attracts monocytes bearing the chemokine receptor CCR-2. Macrophage expression of cyclooxygenase-2, a key enzyme in inflammation, promotes atherosclerotic lesion formation in low-density lipoprotein receptor (LDLR)-deficient mice. In the arterial intima, monocytes differentiate into macrophages, which accumulate cholesterol esters to form lipid-laden foam cells. Foam cell formation can be viewed as an imbalance in cholesterol homeostasis. The uptake of atherogenic lipoproteins is mediated by scavenger receptors, including SR-A and CD36. In the macrophage, ACAT-1 is responsible for esterifying free cholesterol with fatty acids to form cholesterol esters. Surprisingly, deficiency of macrophage ACAT-1 promotes atherosclerosis in LDLR-deficient mice. A number of proteins have been implicated in the process of promoting the efflux of free cholesterol from the macrophage, including apoE, ABCA1, and SRB-1. Macrophage-derived foam cells express the adipocyte fatty acidbinding protein (FABP), aP2, a cytoplasmic FABP that plays an important role in regulating systemic insulin resistance in the setting of obesity. ApoE-deficient mice null for macrophage aP2 expression develop significantly less atherosclerosis than controls wild type for macrophage aP2 expression. These results demonstrate a significant role for macrophage aP2 in the formation of atherosclerotic lesions independent of its role in systemic glucose and lipid metabolism. Furthermore, macrophages deficient in aP2 display alterations in inflammatory cytokine production. Through its distinct actions in adipocytes and macrophages, aP2 links features of the metabolic syndrome including insulin resistance, obesity, inflammation, and atherosclerosis.

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Section: Macrophage Foam Cell Formation and Cholesterol Homeostasismentioning

confidence: 83%

Macrophages, inflammation, and atherosclerosis

2003

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“…Ishibashi and colleagues (52) crossed a different strain of ACAT1 Ϫ/Ϫ mice with LDLR Ϫ/Ϫ and apoE Ϫ/Ϫ mice and found that ACAT1 deficiency was associated with ϳ50% reduction in aortic root lesions in LDLR Ϫ/Ϫ mice and did not decrease serum cholesterol levels (52). However, Fazio et al (58) showed that LDLR Ϫ/Ϫ mice reconstituted with ACAT1 Ϫ/Ϫ macrophages had increased atherosclerotic lesions that contained more free cholesterol and fewer macrophages than control lesions. The apparent discrepancies between these studies may reflect differences in methodology or study design.…”

Section: Minireview: Enzymes Of Neutral Lipid Synthesis 40370mentioning

confidence: 99%

“…The apparent discrepancies between these studies may reflect differences in methodology or study design. Ishibashi and colleagues (52) quantified lesion areas by measuring neutral lipid staining even though the cholesterol ester content of atherosclerotic lesions in ACAT1 Ϫ/Ϫ mice was significantly diminished (56,58). The lesion areas consequently may have been underestimated.…”

Section: Minireview: Enzymes Of Neutral Lipid Synthesis 40370mentioning

confidence: 99%

The Enzymes of Neutral Lipid Synthesis

Buhman¹,

Chen²,

Farese³

2001

Journal of Biological Chemistry

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148

115

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“…Moreover, acceleration of FC accumulation in lesional macrophages in mice by targeted disruption of Soat1 leads to increased lesional macrophage apoptosis (19). FC-induced death in cultured macrophages, like lesional macrophage death in vivo, has both apoptotic and necrotic features (3,4), and it is likely that at least a portion of the necrosis is secondary to defective phagocytic clearance of apoptotic macrophages (postapoptotic necrosis) (20,21).…”

mentioning

confidence: 99%

Niemann-Pick C heterozygosity confers resistance to lesional necrosis and macrophage apoptosis in murine atherosclerosis

Feng

Zhang

Kuriakose

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

131

110

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Macrophage death in advanced atherosclerotic lesions leads to lesional necrosis and likely promotes plaque instability, a precursor of acute vascular events. Macrophages in advanced lesions accumulate large amounts of unesterified cholesterol, which is a potent inducer of macrophage apoptosis. We have shown recently that induction of apoptosis in cultured macrophages requires cholesterol trafficking to the endoplasmic reticulum (ER). Moreover, macrophages from mice with a heterozygous mutation in the cholesterol-trafficking protein Npc1 have a selective defect in cholesterol trafficking to the ER and are protected from cholesterol-induced apoptosis. The goal of the present study was to test the importance of intracellular cholesterol trafficking in atherosclerotic lesional macrophage death by comparing lesion morphology in Npc1 ؉/؉ ;Apoe ؊/؊ and Npc1 ؉/؊ ;Apoe ؊/؊ mice. Although advanced lesions in Npc1 ؉/؉ ;Apoe ؊/؊ mice had extensive acellular areas that were rich in unesterified cholesterol and macrophage debris, the lesions of Npc1 ؉/؊ ;Apoe ؊/؊ mice were substantially more cellular and less necrotic. Moreover, compared with Npc1 ؉/؊ ;Apoe ؊/؊ lesions, Npc1 ؉/؉ ;Apoe ؊/؊ lesions had a greater number of large, TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling)-positive areas surrounding necrotic areas, indicative of macrophage apoptosis. These differences were observed despite similar total lesion area and similar plasma lipid levels in the two groups of mice. These data provide in vivo evidence that intact intracellular cholesterol trafficking is important for macrophage apoptosis in advanced atherosclerotic lesions and that the ERbased model of cholesterol-induced cytotoxicity is physiologically relevant. Moreover, by showing that lesional necrosis can be diminished by a subtle defect in intracellular trafficking, these findings suggest therapeutic strategies to stabilize atherosclerotic plaques.

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Increased atherosclerosis in LDL receptor–null mice lacking ACAT1 in macrophages

Cited by 224 publications

References 43 publications

Macrophages, inflammation, and atherosclerosis

Macrophages, inflammation, and atherosclerosis

The Enzymes of Neutral Lipid Synthesis

Niemann-Pick C heterozygosity confers resistance to lesional necrosis and macrophage apoptosis in murine atherosclerosis

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