Article

Physiological and pathological roles of a multi-ligand receptor CD36 in atherogenesis; insights from CD36-deficient patients

Department of Internal Medicine and Molecular Science, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Molecular and Cellular Biochemistry (Impact Factor: 2.39). 06/2007; 299(1-2):19-22. DOI: 10.1007/s11010-005-9031-4
Source: PubMed

ABSTRACT Oxidized low density lipoprotein (LDL) (Ox-LDL) plays an important role in the pathogenesis of atherosclerosis. Oxidized LDL is taken up by macrophages via scavenger receptors. CD36 is an 88 kDa glycoprotein expressed on platelets, monocyte-macrophages, microvascular endothelial cells, adipose tissue, skeletal muscles and heart. We found patients with CD36 deficiency and identified several mutations in the CD36 gene. We also reported that CD36-deficient macrophages showed a 50% reduction in the binding of Ox-LDL, suggesting that CD36 is one of the major receptors for Ox-LDL. CD36 was expressed on macrophages in the atherosclerotic lesions of human aorta and coronary arteries especially on foamed macrophages. The distribution of CD36 expression was slightly different from that of scavenger receptor class A types I and II. The expression of CD36 on macrophages was up-regulated by Ox-LDL and down-regulated by interferon gamma. Since CD36 is a transporter of long-chain fatty acids (LCFA), CD36-deficient patients showed a defect in the uptake of an LCFA analog, BMIPP, by the heart. Furthermore, the secretion of IL-1beta and TNF-alpha from monocyte-derived macrophages induced by Ox-LDL was markedly reduced and the activation of NF-kappaB was attenuated in CD36-deficient subjects compared with controls, suggesting that CD36-mediated signaling is also impaired in CD36 deficiency. To elucidate the roles of CD36 in vivo, we characterized the clinical profile of CD36-deficient patients. Most of them were accompanied by hyperlipidemia (mainly hypertriglyceridemia), increased remnant lipoproteins and mild elevation of fasting plasma glucose level and blood pressure. Glucose clamp technique revealed mean whole body glucose uptake was reduced in CD36-deficient patients, indicating the presence of insulin resistance. The frequency of CD36 deficiency was higher in patients with coronary heart disease (CHD) than in control subjects. Taken together, CD36 deficiency is accompanied by (1) hyperlipidemia and increased remnant lipoproteins, (2) impaired glucose metabolism based upon insulin resistance, and (3) mild hypertension, and comprises one of the genetic backgrounds of the metabolic syndrome, leading to the development of CHD.

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    • "OxLDL via CD36 induces the activation of other mitogen-activated kinases such as p38 mitogen-activated kinase and ERK 1/2.38 Signaling mediated by CD36 activates nuclear factor kappa beta. CD36-deficient macrophages have reduced nuclear factor kappa beta activation and reduced the release of interleukin (IL)-1β and tumor necrosis factor-α.39 "
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    • "Therefore, PPAR activation is considered to be valuable for prevention and improvement of metabolic syndrome. High serum lipid levels under fasting conditions have been considered a risk of cardiovascular diseases [10]. Many studies have revealed that serum lipid levels under postprandial conditions, rather than under fasting conditions, strongly correlate with the risk of cardiovascular diseases [11]. "
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    • "Mutations resulting in CD36 deficiency occur in humans and some strains of spontaneously hypertensive rats. Humans with CD36 deficiency exhibit hyperlipidemia, increased remnant lipoproteins, impaired glucose metabolism based upon insulin resistance, and mild hypertension [55]. Based on our observation that Aβ impairs the fatty acid translocase activity of CD36, the accumulation of vascular-associated Aβ in Alzheimer's disease could cause a local functional CD36 deficiency by blocking lipid and, potentially, oxidized lipoprotein uptake via this receptor. "
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