Lipid‐induced Insulin Resistance Is Associated With Increased Monocyte Expression of Scavenger Receptor CD36 and Internalization of Oxidized LDL

Abstract

Elevated free fatty acids (FFAs) contribute to the development of insulin resistance, type 2 diabetes mellitus (T2DM), and may be atherogenic. We tested the relationship among lipid-induced insulin resistance, endothelial dysfunction, and monocyte capacity to form foam cells through scavenger receptor A (SRA) and CD36. Ten healthy subjects underwent 24-h infusion of Intralipid/heparin and saline (0.5 ml/min) on two separate occasions followed by brachial artery reactivity testing and a euglycemic hyperinsulinemic (80 mU/(kg·min)) clamp study to determine insulin sensitivity. Isolation of blood monocytes was performed 24 h after infusion. Surface expression and function of CD36 and SRA to take up oxidized low-density lipoprotein (oxLDL) was determined by flow cytometry and quantitative confocal imaging. Lipid infusion resulted in a twofold increase in serum FFA levels, reduced whole-body glucose disposal by ~20% (P < 0.05), and possibly impaired endothelial-dependent vasodilation (P = 0.1). Blood monocytes obtained during lipid infusion demonstrated a ~25% increase in cell surface expression of CD36 (P < 0.05) but no change in SRA expression. Enhanced CD36 expression was associated with a 50% increase in internalization of oxLDL (P < 0.05). The increase in CD36 surface expression during lipid infusion correlated inversely with glucose disposal (P < 0.05) and not with FFA levels or brachial artery dilation. These data support a role for FFAs in induction of insulin resistance and provide a link to atherogenic mechanisms mediated by expression of scavenger receptor CD36.

CD36 Binds Oxidized Low Density Lipoprotein (LDL) in a Mechanism Dependent upon Fatty Acid Binding

“…Because obesity and type 2 diabetes are characterized by high plasmas levels of long chain FA (67,68), the demonstrated enhancement of oxLDL uptake by increases in common dietary FA may contribute to the pathophysiology of these diseases. Our results also support the hypothesis that CD36 may be a link between insulin resistance states from studies showing that increased plasma FA levels were associated with enhanced CD36 expression and increased internalization of oxLDL (69).…”

Type 2 scavenger receptor CD36 in platelet activation: the role of hyperlipemia and oxidative stress

“…Expression decreases rapidly and dramatically after exposure to lipopolysaccharide, dexamethasone or TGF-β [56,61]. In vivo , monocyte CD36 expression levels increase in response to lipid infusion [62]. CD36 expression in macrophages is increased by exposure to hyperglycemia [63,64] and certain HIV protease inhibitor drugs [65].…”

The endocrinology of taste receptors

“…Mice lacking PYY demonstrated considerably reduced preferences for fat taste. 43,59 Moreover, mice lacking CD36 (a lipid sensor that belongs to the scavenger receptor family and binds saturated and unsaturated LCFAs) 79,80 showed no taste preference for LCFA-enriched solutions and solid food, which indicates that CD36 function is an absolute requirement for oral discrimination of LCFAs. 81 PYY might be involved in regulating CD36 expression and/or function; however, this possibility has not yet been studied.…”