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.