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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CD36 protein turnover is decreased in ob/ob macrophages. Pooled WT or ob...
CD36 protein turnover is decreased in ob/ob macrophages. Pooled WT or ob/ob macrophages were pulse-labeled with [35S]methionine/cysteine cell-labeling mix for 20 minutes (A) or 4 hours (B), then chased in medium with methionine/cysteine for the times indicated. 35S-labeled CD36 in total lysates was immunoprecipitated with anti-CD36 and subjected to SDS-PAGE followed by transfer to nitrocellulose membrane and autoradiography. 35S intensities were quantified by densitometric analysis, and each number was normalized for input (measured by Western analysis of β-actin in lysates), then to the relative intensity at chase time 0 hours. For 20-minute and 4-hour labeling experiments, one experiment representative of two and four independent experiments, respectively, is shown. Macrophages were isolated from five to seven mice of each strain.