The receptor tyrosine kinase Ron attenuates obesity-induced atherosclerosis progression and liver injury by down-regulating inflammation in ApoE-/- mice (54.16)

Abstract

Abstract Obesity and its associated metabolic diseases are leading causes of death worldwide. Obesity increases the likelihood of atherosclerosis, diabetes and hepatic steatosis, which are caused largely by macrophage activation at aorta, adipose tissue and liver, respectively. Macrophages are classified as classical activated macrophages(M1), which are associated with increased inflammatory mediators, and alternative activated macrophages(M2), which are associated with decreased inflammation and tissue repair. Recent studies suggest M2 predominate in non-inflamed tissue in lean animals, while either a switch from M2 to M1 or direct recruitment of M1 in aorta and adipose tissue promotes atherosclerosis and insulin resistance progression. Our previous studies show that the Ron receptor tyrosine kinase, expressed primarily on tissue-resident macrophages, inhibits hallmarks of M1 activation and skews populations towards an M2 phenotype both in vitro and in vivo. Here, we show that the absence of Ron results in increased severity of atherosclerosis and liver injury, which is accompanied by elevated expression of inflammatory markers in aortas and livers in ApoE-/- X Ron-/- mice on a high cholesterol diet. However, we failed to detect significant differences in glucose tolerance or fatty acid metabolism. Our results indicate Ron plays a central role in limiting obesity-induced inflammation and plays a protective role in the progression of atherosclerosis and hepatic steatosis.