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Macrophage Liver Kinase B1 Inhibits Foam Cell Formation and Atherosclerosis.

ABSTRACT: RATIONALE:LKB1 (liver kinase B1) is a serine/threonine kinase and tumor suppressor, which regulates the homeostasis of hematopoietic cells and immune responses. Macrophages transform into foam cells upon taking-in lipids. No role for LKB1 in foam cell formation has previously been reported. OBJECTIVE:We sought to establish the role of LKB1 in atherosclerotic foam cell formation. METHODS AND RESULTS:LKB1 expression was examined in human carotid atherosclerotic plaques and in western diet-fed atherosclerosis-prone Ldlr-/- and ApoE-/- mice. LKB1 expression was markedly reduced in human plaques when compared with nonatherosclerotic vessels. Consistently, time-dependent reduction of LKB1 levels occurred in atherosclerotic lesions in western diet-fed Ldlr-/- and ApoE-/- mice. Exposure of macrophages to oxidized low-density lipoprotein downregulated LKB1 in vitro. Furthermore, LKB1 deficiency in macrophages significantly increased the expression of SRA (scavenger receptor A), modified low-density lipoprotein uptake and foam cell formation, all of which were abolished by blocking SRA. Further, we found LKB1 phosphorylates SRA resulting in its lysosome degradation. To further investigate the role of macrophage LKB1 in vivo, ApoE-/-LKB1fl/flLysMcre and ApoE-/-LKB1fl/fl mice were fed with western diet for 16 weeks. Compared with ApoE-/-LKB1fl/fl wild-type control, ApoE-/-LKB1fl/flLysMcre mice developed more atherosclerotic lesions in whole aorta and aortic root area, with markedly increased SRA expression in aortic root lesions. CONCLUSIONS:We conclude that macrophage LKB1 reduction caused by oxidized low-density lipoprotein promotes foam cell formation and the progression of atherosclerosis.

SUBMITTER: Liu Z

PROVIDER: S-EPMC5640502 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Macrophage Liver Kinase B1 Inhibits Foam Cell Formation and Atherosclerosis.

Liu Zhaoyu Z Zhu Huaiping H Dai Xiaoyan X Wang Cheng C Ding Ye Y Song Ping P Zou Ming-Hui MH

Circulation research 20170821 9

<h4>Rationale</h4>LKB1 (liver kinase B1) is a serine/threonine kinase and tumor suppressor, which regulates the homeostasis of hematopoietic cells and immune responses. Macrophages transform into foam cells upon taking-in lipids. No role for LKB1 in foam cell formation has previously been reported.<h4>Objective</h4>We sought to establish the role of LKB1 in atherosclerotic foam cell formation.<h4>Methods and results</h4>LKB1 expression was examined in human carotid atherosclerotic plaques and in ...[more]

PMID: 28827412

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Project description:ObjectiveBy binding to its high-affinity receptor FcεR1, IgE activates mast cells, macrophages, and other inflammatory and vascular cells. Recent studies support an essential role of IgE in cardiometabolic diseases. Plasma IgE level is an independent predictor of human coronary heart disease. Yet, a direct role of IgE and its mechanisms in cardiometabolic diseases remain incompletely understood. Approach and Results: Using atherosclerosis prone Apoe-/- mice and IgE-deficient Ige-/- mice, we demonstrated that IgE deficiency reduced atherosclerosis lesion burden, lesion lipid deposition, smooth muscle cell and endothelial cell contents, chemokine MCP (monocyte chemoattractant protein)-1 expression and macrophage accumulation. IgE deficiency also reduced bodyweight gain and increased glucose and insulin sensitivities with significantly reduced plasma cholesterol, triglyceride, insulin, and inflammatory cytokines and chemokines, including IL (interleukin)-6, IFN (interferon)-γ, and MCP-1. From atherosclerotic lesions and peritoneal macrophages from Apoe-/-Ige-/- mice that consumed an atherogenic diet, we detected reduced expression of M1 macrophage markers (CD68, MCP-1, TNF [tumor necrosis factor]-α, IL-6, and iNOS [inducible nitric oxide synthase]) but increased expression of M2 macrophage markers (Arg [arginase]-1 and IL-10) and macrophage-sterol-responsive-network molecules (complement C3, lipoprotein lipase, LDLR [low-density lipoprotein receptor]-related protein 1, and TFR [transferrin]) that suppress macrophage foam cell formation. These IgE activities can be reproduced in bone marrow-derived macrophages from wild-type mice, but muted in cells from FcεR1-deficient mice, or blocked by anti-IgE antibody or complement C3 deficiency.ConclusionsIgE deficiency protects mice from diet-induced atherosclerosis, obesity, glucose tolerance, and insulin resistance by regulating macrophage polarization, macrophage-sterol-responsive-network gene expression, and foam cell formation.

Dataset Information

Macrophage Liver Kinase B1 Inhibits Foam Cell Formation and Atherosclerosis.

Publications

Macrophage Liver Kinase B1 Inhibits Foam Cell Formation and Atherosclerosis.

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