Increased CD36 protein as a response to defective insulin signaling in macrophages
Chien-Ping Liang, … , Domenico Accili, Alan R. Tall
Chien-Ping Liang, … , Domenico Accili, Alan R. Tall
Published March 1, 2004
Citation Information: J Clin Invest. 2004;113(5):764-773. https://doi.org/10.1172/JCI19528.
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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

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The expression and signaling of insulin receptor is downregulated in ob/...
The expression and signaling of insulin receptor is downregulated in ob/ob versus WT macrophages. (A) Insulin receptor β-subunit (IRβ) expression is decreased in pooled ob/ob compared with WT macrophages isolated from six mice of each strain, as determined by Western analysis. One experiment representative of three independent experiments is shown. A similar expression pattern is also found in ob/ob liver. (B and C) Insulin-dependent tyrosine phosphorylation of IR (B) and IRS-2 (C) in ob/ob macrophages is defective, even at a higher insulin concentration (10 nM) than ob/ob plasma insulin levels (about 4 nM). Ex vivo tyrosine phosphorylation of IR or IRS-2 by IR tyrosine kinase in response to insulin in 32P-preincubated pooled ob/ob and WT macrophages isolated from five mice each was performed for 10 minutes. Total protein lysates were then subjected to immunoprecipitation with anti-IR or anti-phosphotyrosine (αP-Tyr) and separated by SDS-PAGE followed by membrane transfer and 32P autoradiography. The membranes were then probed with anti–P-Tyr or anti-IR (for IR) or with anti–IRS-2, respectively. In C (bottom), P-Tyr p30 whose tyrosine phosphorylation status was not affected by insulin is shown to reflect the amounts of initial extracts used for immunoprecipitation of phosphoproteins. One experiment representative of two independent experiments is shown. IP, immunoprecipitation; IB, immunoblotting.