A Central Role for CD36 in Mediating Oxidized LDL and Fatty Acid Induced Insulin Resistance

Abstract

Elevated levels of oxidized LDL (oxLDL) and fatty acids (FA) are highly associated with insulin resistance. Clinical and experimental evidence also demonstrate increased expression of scavenger receptor CD36 in insulin resistant states. As oxLDL and FA are CD36 ligands, we tested the hypothesis that they influence insulin resistance in a CD36 dependant manner.3T3‐L1 adipocytes treated with oxLDL or with FA showed time and dose dependent increases in CD36 expression, activated Jun kinase (JNK), induced inhibitory IRS‐1 serine phosphorylation, increased adipocyte lypolysis and decreased glucose uptake. Pre‐incubation with either a CD36 monoclonal antibody or JNK kinase inhibitor attenuated these changes.Next, ApoE null mice with or without a CD36 null mutation (CD36+ or CD36−) were fed a high fat diet for 12 weeks and examined for physiologic and biochemical markers of insulin resistance. These mice have increased oxLDL and FA levels and their isolated lipoproteins are CD36 ligands, inducing CD36‐dependent foam cell formation and atherosclerosis. Compared with CD36+ mice, CD36− mice had improved glucose clearance, decreased JNK activation and IRS‐1 serine phosphorylation in adipose tissue, increased AKT activation in both liver and muscle, as well as increased levels of adiponectin in adipose, muscle and liver.These data suggest a central role for CD36 in mediating oxLDL and FA induced insulin resistance.