Macrophage Liver Kinase B1 Inhibits Foam Cell Formation and Atherosclerosis.

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, ApoELKB1LysM and ApoELKB1 mice were fed with western diet for 16 weeks. Compared with ApoELKB1 wild-type control, ApoELKB1LysM 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.