CD36, oxidized LDL and PPARγ: pathological interactions in macrophages and atherosclerosis

doi:10.1016/j.vph.2004.08.003

Vascular Pharmacology

Volume 41, Issues 4–5, May–June 2004, Pages 139-146

https://doi.org/10.1016/j.vph.2004.08.003 Get rights and content

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Relative roles of CD36 and SR-A in atherosclerosis

Endemann et al. (1993) used an expression cloning strategy to identify murine macrophage receptors that recognized OxLDL but not acetylated LDL. They identified the murine homologue of CD36 (platelet gpIV). CD36 is a member of family of receptors that also includes SR-B1/CLA-1, a HDL receptor (Acton et al., 1996, Calvo and Vega, 1993). CD36 was originally identified as a platelet membrane glycoprotein and a receptor for thrombospondin (TSP-1) (Li et al., 1993). It is also expressed by

Lipid ligands of CD36

Much interested has been focused on the components of OxLDL that are recognized by and bind to macrophage scavenger receptors. CD36 recognizes lipid moities of OxLDL. This is in contrast to SR-A, which recognizes the oxidized apoprotein portion of the lipoprotein particle (Parthasarathy et al., 1987). Several years ago, we demonstrated that delipidated ¹²⁵I-labeled OxLDL did not bind to CD36-transfected cells, whereas delipidated OxLDL will bind to SR-A (Nicholson et al., 1995). Anionic

Regulation of CD36

Foam cell will not develop in macrophages cultured with high levels of native LDL because high cellular cholesterol levels down-regulate LDL-receptor gene transcription. This pathway does not inhibit scavenger receptors, but the role of lipids in regulating expression of scavenger receptors was not tested until we studied the effect of lipoproteins on the expression of CD36 in J774 cells, a murine macrophage cell line (Han et al., 1997). Exposure to OxLDL resulted in a marked induction of CD36

Effects of thiazolidinediones on CD36 and atherosclerosis

The thiazolidinedione (TZD) class of insulin sensitizing drugs is used for the treatment of type 2 diabetes. Because of the potential adverse effect of up-regulation of CD36 in response to these PPARγ agonists, it was important to determine the effects of TZDs on macrophage foam cell formation and atherosclerosis. Treatment of macrophage cell lines with troglitazone and LG268 (an RXR agonist) led to a significant increase in binding and uptake of OxLDL (Tontonoz et al., 1998). In contrast,

Effects of statins on CD36

Inhibition of scavenger receptor expression is one potential mechanism by which hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may modulate atherosclerotic lesion formation. While inhibition of cholesterol synthesis in the liver is the primary mechanism by which statins exert their atherosclerotic effects, statins also have pleotrophic effects that are distinct from their cholesterol-lowering actions. We, and others, have shown that statins inhibit macrophage

Insulin resistance and diabetes

The role and regulation of CD36 in diabetes and insulin resistance has been addressed by several groups, but is controversial. It is clear that both microvascular and macrovascular disease are accelerated in diabetic patients. In fact, type 2 diabetics have a three-fold increased risk of developing coronary artery disease. However, the cause of accelerated atherosclerosis is poorly understood. CD36 was identified as an insulin-resistance gene causing defective fatty acid and glucose metabolism

HDL inhibits CD36 through phosphorylation of PPARγ

Because of CD36 is a potential therapeutic target for atherosclerosis, an understanding of mechanisms to inhibit or down-regulate its expression is important. LPS, dexamethasone, interferon-γ and TGF-β inhibit expression of CD36 (Yesner et al., 1996, Nakagawa et al., 1998, Han et al., 2000). We tested the hypothesis that HDL could modulate PPARγ-responsive genes by acting as a cholesterol acceptor particle. We had previously demonstrated that removal (efflux) of cholesterol with cyclodextrin (a

Acknowledgements

This work was supported by a National Institutes of Health Grant NIH P01-HL072942 (ACN and DPH). Additional support was provided by the Rosanne H. Silbermann Foundation (ACN).

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This observation can explain why PA did not upregulate CD36 expression, due to its inability to activate PPAR-γ. However, the high expression of CD36, produced especially with EA, indicates a high uptake of oxidized lipoproteins [61], which consequently contributes to macrophage conversion to foam cells [62]. We showed that elevated levels of EA could increase the uptake of FA in human monocytes and subsequently induce smooth cell formation, as shown by transmission electron microscopy, which could in turn accelerate the development of atherosclerotic lesions through CD36.
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