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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Lack of insulin receptors in peritoneal macrophages leads to upregulatio...
Lack of insulin receptors in peritoneal macrophages leads to upregulation of CD36 protein expression and oxLDL binding. (A) Western analysis of macrophage IRβ subunit, IRS-2, CD36, SR-A, and SR-BI protein expression in IR knockout (IR-KO) mice rescued with the human IR transgene and in control littermate (IR+/+) mice. Both CD36 and SR-A protein are increased in IR-deficient macrophages. (B) Northern analysis of CD36 and SR-A mRNA levels in macrophages of IR-KO and IR+/+ mice. (C) Assay of oxLDL binding to macrophages from IR-KO and control IR+/+ was carried out with or without the addition of fucoidan (50 μg/ml), mouse anti-CD36 IgA (20 μg/ml), or control IgA (20 μg/ml; not shown) in the binding buffer. CD36-depend. and SR-A–depend., oxLDL binding mediated by CD36 and SR-A, respectively. All experiments were performed with pooled macrophages isolated from three to five mice of each strain. One experiment representative of three independent experiments is shown.