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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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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Treatment of ob/ob mice with rosiglitazone improves insulin resistance a...
Treatment of ob/ob mice with rosiglitazone improves insulin resistance and normalizes oxLDL binding and CD36 protein expression in macrophages. (A) In vivo rosiglitazone (RSG) treatment reduces plasma glucose levels and oxLDL binding to macrophages in ob/ob mice. Plasma glucose levels (left) and macrophage oxLDL binding (right) were assessed in ob/ob mice treated with rosiglitazone or control saline. At the times indicated, plasma glucose levels from these mice were measured. After 3 weeks, macrophages were collected and an oxLDL binding assay was performed with the addition of fucoidan (50 μg/ml) in the binding buffer. (B) Differential patterns of CD36 protein expression in ob/ob macrophages in response to thiazolidinedione treatments in vivo and ex vivo. Left, Western analysis of CD36 protein expression in ob/ob and WT macrophages treated ex vivo with RSG or troglitazone (TRG) at the indicated doses for 1 day. Right, the expression of CD36 and IR β-subunit (IRβ) protein in macrophages from ob/ob mice described in A was determined by Western analysis. Macrophage CD36 protein was normalized in ob/ob mice, though its mRNA was increased by rosiglitazone in vivo, as measured by Northern analysis. Macrophage experiments were performed with pooled cells isolated from three to five mice of each strain indicated. One experiment representative of two independent experiments is shown.