Role of CD36, the Macrophage Class B Scavenger Receptor, in Atherosclerosis

Nicholson, Andrew C.; Han, Jihong; Febbraio, Maria; Silversterin, Roy L.; Hajjar, David P.

doi:10.1111/j.1749-6632.2001.tb03944.x

Cited by 123 publications

(80 citation statements)

References 45 publications

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“…5,6,32 The findings in the current study that showed that freshly isolated DKO peritoneal macrophages exhibited decreased neutral lipid staining, decreased CD36 mRNA levels and that the DKO mice had decreased atherosclerosis are consistent with these previous studies. However, additional studies will be necessary as the link between CD36 expression and atherosclerosis has recently been challenged by Moore et al; these authors reported that Cd36 Ϫ/Ϫ Apoe Ϫ/Ϫ mice exhibited increased aortic sinus lesions, even though the DKO peritoneal macrophages exhibited reduced lipid accumulation in vitro.…”

Section: Discussionsupporting

confidence: 80%

FXR Deficiency Causes Reduced Atherosclerosis inLdlr^−/−Mice

Zhang

Wang

Vales

et al. 2006

ATVB

150

107

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Objective-Based on the observation that Fxr Ϫ/Ϫ mice exhibit a proatherogenic lipoprotein profile, we investigated the role of FXR in the development of atherosclerosis. Methods and Results-Administration of a western diet to FxrϪ/Ϫ mice or wild-type mice does not result in the development of significant atherosclerotic lesions. Consequently we generated Fxr Ϫ/Ϫ Ldlr Ϫ/Ϫ (DKO) mice and compared lesion development with Ldlr Ϫ/Ϫ mice. After 16 weeks on a Western diet, en face analysis of the aorta indicated that the male DKO mice had reduced atherosclerotic lesions as compared with Ldlr Ϫ/Ϫ mice. Plasma low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels were reduced by 40% to 50%, whereas triglyceride levels increased 4-fold in the male DKO mice. Finally, peritoneal macrophages freshly isolated from male DKO mice had reduced expression of CD36 mRNA and decreased neutral lipid accumulation, as compared with Ldlr Ϫ/Ϫ mice. Conclusions-FXR deficiency in male, but not female, Ldlr Ϫ/Ϫ mice results in a reduction in the size of atherosclerotic lesions in the aorta. The reduction in atherosclerosis may result from a decrease in plasma low-density lipoprotein cholesterol, coupled with reduced expression of CD36 in macrophages of DKO mice. Key Words: atherosclerosis Ⅲ cholesterol Ⅲ FXR Ⅲ LDLR Ⅲ nuclear receptor A therosclerosis is a chronic inflammatory disease, characterized by accumulation of lipids and fibrous elements in the walls of large arteries. 1 It is well-established that high-plasma low-density lipoprotein cholesterol (LDL-C) level is an independent risk factor for the development of atherosclerosis. High levels of LDL-C are thought to result in the generation of oxidized (ox) and aggregated LDL in the subendothelial areas of the arterial wall. Ox-LDL contains bioactive lipids that promote the entry of monocytes into the subendothelial space, where they differentiate into macrophages. These macrophages then take up ox-LDL and/or aggregated LDL via scavenger receptors (CD36 or SR-A) or phagocytosis. The result is the generation of lipid-engorged macrophages (also called foam cells) that are found in the early fatty streak as well as more complex advanced lesions. [1][2][3] The role of CD36 in atherosclerotic lesion development has become controversial. Original studies showed that a null mutation of CD36 in mice impaired the conversion of peritoneal macrophages to foam cells. 4 Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that is highly expressed in liver, intestine, kidney, and adrenal gland, 7 with very low levels (Ϸ10%) being detected in white adipose tissue. 8 FXR is activated by specific bile acids that include chenodeoxycholic acid (CDCA) and cholic acid, 9 -11 and also structurally unrelated synthetic compounds, such as GW4064 12 and fexaramine. 13 FXR plays an important role in maintaining bile acid, cholesterol, triglyceride, and glucose homeostasis. 12,14 -18 Importantly, plasma cholesterol and triglyceride levels are increased in Fxr Ϫ/Ϫ ...

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Section: Discussionsupporting

confidence: 80%

FXR Deficiency Causes Reduced Atherosclerosis inLdlr^−/−Mice

Zhang

Wang

Vales

et al. 2006

ATVB

150

107

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“…Besides being a FA transporter, CD36 acts as scavenger receptor, the major receptor for oxLDL in macrophages [30]. Furthermore, CD36 has been previously demonstrated to internalize oxLDL in adipocytes, suggesting that they can function as phagocytes, like macrophages, and that might participate in the clearance of circulating oxLDL [10].…”

Section: Discussionmentioning

confidence: 99%

Oxidised LDL up‐regulate CD36 expression by the Nrf2 pathway in 3T3‐L1 preadipocytes

et al. 2008

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The effect of oxLDL on CD36 expression has been assessed in preadipocytes induced to differentiate. Novel evidence is provided that oxLDL induce a peroxisome proliferator-activated receptor c-independent CD36 overexpression, by up-regulating nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2). The nuclear translocation of Nrf2 appeared to depend on PKC pathway activation. In adipocytes, the CD36 up-regulation may indicate a compensation mechanism to meet the demand of excess oxLDL and oxidised lipids in blood, reducing the risk of atherogenesis. Besides strengthening the hypothesis that oxLDL can contribute to the onset of insulin-resistance, data herein presented highlight the significance of oxLDL-induced CD36 overexpression within the cellular defence response.

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“…MΦ uptake of OxLDL provides ligands for PPARγ, including 9-HODE and 13-HODE [46,171]. The mechanism by which OxLDL upregulates CD36 appears to involve activation of PPARγ [172] and PPARα [173]. PPARγ is induced in human monocytes following exposure to OxLDL and is expressed at high levels in foam cells [48].…”

Section: Interrelationship Between Eicosanoids Ppars and Stimulationmentioning

confidence: 99%

Macrophage Differentiation to Foam Cells

Shashkin¹,

Dragulev²,

Ley³

2005

CPD

245

159

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Foam cell formation from macrophages with subsequent fatty streak formation plays a key role in early atherogenesis. Foam cell formation is thought to be induced by Low Density Lipoproteins (LDL), including oxidized LDL (OxLDL) or minimally modified LDL (mmLDL). Understanding the molecular mechanisms involved in OxLDL-and mmLDL-induced foam cell formation is of fundamental importance for atherosclerosis and cardiovascular disease. The expression of many genes is likely modulated during macrophage transformation into a foam cell. In this mini-review we describe functional consequences of modulation of three groups of genes: Scavenger Receptors (SR-A, CLA-1/SR-BI, CD36, CD68, LOX-1, and SR-PSOX), the PPAR family of nuclear receptors, and a number of genes involved in eicosanoid biosynthesis, including lipoxygenases and leukotriene receptors. Scavenger receptors appear to play a key role in uptake of OxLDL, while mmLDL appears to interact with CD14/TLR4. The regulation of scavenger receptors is, in part, mediated by the PPAR family of nuclear receptors. PPARα and PPARγ agonists, such as thiazolidinediones and fibrates, and PPARδ agonists were tested as atheroprotective drugs and showed some beneficial effects. Eicosanoids are naturally occuring agonists for PPARs. Recent observations indicate a role of the components of the eicosanoid cascade, such as 5-lipoxygenase, 15-lipoxygenase and the leukotriene receptors in foam cell formation. Selective inhibitors of lipoxygenases and leukotriene receptors could be useful in the treatment of atherosclerosis by preventing or reducing foam cell formation.

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Role of CD36, the Macrophage Class B Scavenger Receptor, in Atherosclerosis

Cited by 123 publications

References 45 publications

FXR Deficiency Causes Reduced Atherosclerosis inLdlr^−/−Mice

FXR Deficiency Causes Reduced Atherosclerosis inLdlr^−/−Mice

Oxidised LDL up‐regulate CD36 expression by the Nrf2 pathway in 3T3‐L1 preadipocytes

Macrophage Differentiation to Foam Cells

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Role of CD36, the Macrophage Class B Scavenger Receptor, in Atherosclerosis

Cited by 123 publications

References 45 publications

FXR Deficiency Causes Reduced Atherosclerosis inLdlr−/−Mice

FXR Deficiency Causes Reduced Atherosclerosis inLdlr−/−Mice

Oxidised LDL up‐regulate CD36 expression by the Nrf2 pathway in 3T3‐L1 preadipocytes

Macrophage Differentiation to Foam Cells

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FXR Deficiency Causes Reduced Atherosclerosis inLdlr^−/−Mice

FXR Deficiency Causes Reduced Atherosclerosis inLdlr^−/−Mice