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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Figure 1

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Enhanced uptake of modified LDL in ob/ob versus WT mouse peritoneal macr...
Enhanced uptake of modified LDL in ob/ob versus WT mouse peritoneal macrophages is mediated by increases in cell surface expression of CD36 and SR-A. (A–C) [125I,3H]acLDL cell association (A), degradation (B), and cholesteryl ester formation (C) are higher in ob/ob than in WT macrophages following acLDL loading. One representative experiment of three independent experiments each using pooled macrophages from five WT and seven ob/ob mice is shown. Short-term treatment (5 hours) of macrophages with either insulin or leptin does not change these parameters. C → CE (vertical axis, C), cholesterol to cholesteryl ester. (D) Protein expression of scavenger receptors CD36 and SR-A is increased while SR-BI expression is decreased in ob/ob versus WT macrophages, as determined by Western analysis (left). Protein extracts were prepared from pooled macrophages of five WT and five ob/ob mice. One experiment representative of four independent experiments is shown. CD36 and SR-A mRNA was not upregulated in ob/ob versus WT macrophages, as shown by Northern analysis (right). Northern analysis was performed with random-primed CD36, SR-A, and actin cDNA probes using total RNA isolated from pooled macrophages of ten mice of each strain. One experiment representative of three independent experiments is shown. (E) Specific binding of oxLDL to ob/ob macrophages is elevated. (F) Effects of fucoidan and anti-CD36 antibody on oxLDL binding to ob/ob and WT macrophages. [125I]oxLDL binding assays were performed with pooled macrophages isolated from five mice of each strain, preincubated with the SR-A ligand fucoidan (20 μg/ml), mouse anti–CD36 IgA (20 μg/ml), or mouse control IgA (20 μg/ml, not shown). The decreases in total oxLDL binding in the presence of CD36 IgA or fucoidan were considered as binding mediated by CD36 or SR-A, respectively. CD36 contributes more to the increase in oxLDL binding to ob/ob versus WT macrophages than SR-A. One experiment representative of three independent experiments is shown. CD36-depend. and SR-A depend., oxLDL binding mediated by CD36 and SR-A, respectively.