Abstract 829: Reduction in Macrophage Lipid Burden by Transgenic Expression of Human Macrophage Cholesteryl Ester Hydrolase Significantly Attenuates Inflammation in LDLR−/− mice
Under hypercholesterolemic conditions, accumulation of intracellular cholesteryl esters (CE) in macrophages leads to the formation of foam cells that secrete high levels of pro-inflammatory mediators. Cholesteryl ester hydrolase (CEH) catalyses the hydrolysis of intracellular CE and we have demonstrated that over-expression of CEH results in mobilization of CE resulting in reduced lipid burden. In the present study we tested the hypothesis that transgenic expression of human CEH would reduce macrophage CE content and thus attenuate systemic inflammation and the associated metabolic pathologies. Control (LDLR−/−) and transgenic (LDLR−/−CEHTg) mice were fed a high-fat high-cholesterol diet for 16 weeks. Circulating cytokine levels were measured as an index of inflammation. The levels of pro-inflammatory cytokines (TNFα, IL1β, MCP1, IL-6 and GM-CSF) were significantly higher in LDLR−/− mice compared to LDLR−/−CEHTg mice (See Figure⇓). Consistent with these increased levels, increased infiltration of macrophages was observed in epididymal adipose tissue indicating that with similar adiposity, the adipose tissue is highly inflamed in LDLR−/− mice. One of the metabolic consequences of inflamed fat, peripheral insulin resistance was evaluated by intra-peritoneal glucose and insulin tolerance tests. LDLR−/−CEHTg mice showed an improved glucose tolerance and a significantly higher rate of glucose disappearance in response to insulin indicating improved insulin sensitivity. Thus, CEH-mediated reduction in macrophage CE levels significantly attenuate systemic inflammation and associated pathologies such as adipose tissue inflammation and insulin resistance.