Abstract 1095: Macrophage-specific Over-expression of Cholesteryl Ester Hydrolase in ob/ob Mice Reduces Hepatic Cholesterol Accumulation and Improves Insulin Sensitivity
Neutral Cholesteryl Ester Hydrolase (CEH) releases free cholesterol from cellular cholesteryl ester (CE) stores and reduces cellular CE burden. Macrophage specific transgenic expression of CEH not only results in attenuated diet-induced atherosclerosis in ldlr deficient mice but also improves insulin sensitivity in this model. To obtain further evidence for the role of CEH and macrophage cholesterol homeostasis in regulating insulin sensitivity, we crossed CEH transgenic mice with leptin deficient ob/ob mice - an established model of insulin resistance. Littermates (ob/ob or ob/obCEHTg) were fed 0.2% cholesterol containing chow diet for 4 weeks and insulin sensitivity determined by intraperitoneal glucose tolerance test. Transgenic expression of CEH significantly improved insulin sensitivity in ob/obCEHTg mice compared to non-transgenic ob/ob mice (see Figure⇓). Although there was no significant difference in the body weight or visceral adipose tissue mass, there was significantly less infiltration of macrophages into the adipose tissue of CEHTg mice demonstrating reduced adipose tissue inflammation. In addition, there was a significant decrease in hepatic triglyceride (31.78±4.16 vs 23.45±4.23 ug/mg, p=0.006) as well as total cholesterol accumulation (26.59±3.02 vs 13.58±1.42 ug/mg, p=2.9E-6) in CEHTg mice indicating attenuation of hepatic steatosis. These studies demonstrate that by regulating macrophage cholesterol homeostasis, CEH regulates adipose tissue inflammation as well as hepatic steatosis and thus improves insulin sensitivity. Direct effects of CEH over-expressing macrophage on insulin signaling and glucose uptake will be discussed.