Increased CD36 protein as a response to defective insulin signaling in macrophages
Chien-Ping Liang, Seongah Han, Haruka Okamoto, Ronald Carnemolla, Ira Tabas, Domenico Accili, Alan R. Tall
Chien-Ping Liang, Seongah Han, Haruka Okamoto, Ronald Carnemolla, Ira Tabas, Domenico Accili, Alan R. Tall
View: Text | PDF
Article Metabolism

Increased CD36 protein as a response to defective insulin signaling in macrophages

Abstract

Accelerated atherosclerosis is a major cause of morbidity and death in insulin-resistant states such as obesity and the metabolic syndrome, but the underlying mechanisms are poorly understood. We show that macrophages from obese (ob/ob) mice have increased binding and uptake of oxidized LDL, in part due to a post-transcriptional increase in CD36 protein. Macrophages from ob/ob mice are also insulin resistant, as shown by reduced expression and signaling of insulin receptors. Three lines of evidence indicate that the increase in CD36 is caused by defective insulin signaling: (a) Treatment of wild-type macrophages with LY294002, an inhibitor of insulin signaling via PI3K, results in an increase in CD36; (b) insulin receptor knockout macrophages show a post-transcriptional increase in CD36 protein; and (c) administration of thiazolidinediones to intact ob/ob mice and ob/ob, LDL receptor–deficient mice results in a reversal of macrophage insulin receptor defects and decreases CD36 protein. The last finding contrasts with the increase in CD36 that results from treatment of macrophages with these drugs ex vivo. The results suggest that defective macrophage insulin signaling predisposes to foam cell formation and atherosclerosis in insulin-resistant states and that this is reversed in vivo by treatment with PPAR-γ activators.

Authors

Chien-Ping Liang, Seongah Han, Haruka Okamoto, Ronald Carnemolla, Ira Tabas, Domenico Accili, Alan R. Tall

×

Figure 6

Options: View larger image (or click on image) Download as PowerPoint
Defects in insulin signaling in mouse macrophages increase oxLDL binding...
Defects in insulin signaling in mouse macrophages increase oxLDL binding and CD36 protein expression. (A) Ex vivo effects of chronic high-dose insulin on insulin receptor β-subunit (far left) and CD36 protein expression (middle panels), and oxLDL binding to WT and ob/ob macrophages (far right). Macrophages were incubated with (+) or without (–) insulin (200 nM) for 1 day. Cells were used for oxLDL binding assays or Western analysis with the indicated antibodies. (B) The increase in CD36 protein expression in WT macrophages by the PI3 kinase inhibitor wortmannin is dose dependent. WT or ob/ob macrophages were treated with wortmannin at the indicated concentrations or another inhibitor, LY294002 (LY; 10 μM), for 1 day, followed by protein extraction and Western analysis (left) and by oxLDL binding assays with fucoidan (50 μg/ml) in the binding buffer (right). Inhibition of the insulin receptor effector PI3 kinase results in an increase in oxLDL binding to macrophages. (C) TNF-α has no effect on CD36 protein expression. WT macrophages were treated with LY294002 (LY; 10 μM) or TNF-α (10 ng/ml) for 1 day. Total lysates were prepared and Western analysis was performed. (D) CD36 protein expression is reduced by 10% FBS in ob/ob and WT macrophages. Insulin receptors are increased under this condition. All experiments were performed with pooled macrophages isolated from three to six mice of each strain indicated. One experiment representative of three independent experiments is shown.