Lectin-like oxidised low density lipoprotein 1 scavenger receptor regulation of signal transduction in cell function and atherosclerosis

Since the discovery of the lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) by Sawamura and colleagues in 1997, this multi-ligand receptor has been implicated in atherosclerosis and diabetes. Oxidised LDL binding and trafficking via LOX-1 cause the activation of downstream signal transduction that cause pro-athrogenic changes such as endothelial dysfunction, apoptosis and foam cell formation. However, the molecular mechanisms have not be been fully explained. In this study, tetracycline- inducible cell lines expressing LOX-1 wild-type and trafficking-defective LOX-1-D5A were developed. The findings show different trafficking properties between LOX-1-WT and LOX-1-D5A in response to oxidised LDL. Due to these differences, LOX-1-WT and LOX-1-D5A in response to oxidised LDL exhibited differential downstream signal transduction. Moreover, 24 hour stimulation of oxidised LDL via LOX-1-WT caused decreased endothelial cell permeability; however, the underlying mechanism is not clear. The impact of deleting LOX-1 in ApoE knockout mice was reduced aortic plaque coverage. This study revealed that pro- atherogenic signal transduction was reduced in aorta in LOX-1/ApoE double knockout mice compared to ApoE knockout mice. Furthermore, the same pro-atherogenic signal transduction was increased in the liver of LOX-1/ApoE knockout mice. The differential signal transduction outcomes in the aorta or liver are dependent on the status of the atherosclerosis disease. LOX-1 is reported to play a role in glucose and lipid homeostasis. Previously, deleting LOX-1 revealed altered glucose metabolism and insulin resistance phenotype. In this study, differences in downstream insulin signalling pathways were exhibited in the skeletal muscle and adipose tissue of LOX-1 knockout and wild-type mice. Experimental findings also revealed the influence of LOX-1 genotype in iron metabolism in the liver. This work has provided insights on a potential role of LOX-1 clearing oxidised LDL from the circulation, and for the first time, this study potentially showed the role of LOX-1 in glucose homeostasis and iron metabolism.