Abstract 1367: Tissue-specific Liver X Receptor Activation Promotes Macrophage Reverse Cholesterol Transport in vivo
Reverse cholesterol transport (RCT) is a crucial pathway for excess cholesterol from macrophages to liver, following by excretion into bile and feces. We have already reported that a systemic liver X receptor (LXR) agonist promotes macrophage RCT in vivo. However, LXR agonists can increase hepatic triglyceride synthesis and causes fatty liver and hypertriglyceridemia. We tested the hypothesis that tissue-specific LXR activation could activate RCT without liver side-effects. Thus, we analyzed the effect of tissue-specific LXR effects on RCT, especially in the small intestine and macrophages. To evaluate the effect of LXR activation in the small intestine on RCT, wild-type mice were treated with either vehicle, GW3965 (systemic agonist), or GW6340 (intestine-specific agonist), followed by in vivo RCT study. GW6340 induced LXR-target gene exclusively in the small intestine, and showed no effect in the liver. Administration of both GW3965 and GW6340 significantly increased [3H]-sterol movement from macrophage to feces. To evaluate the effect of macrophage LXR, we used LXRα/β deficiency mice and primary macrophages deficient in LXR expression; macrophage-specific LXR expression showed no significant change, but macrophage-specific LXR deficiency significantly reduced fecal [3H]-sterol counts. In conclusion, we demonstrate that the intestine-specific LXR agonist promotes RCT in vivo without liver-related side effects, and macrophage LXR plays an important role in promoting RCT. Based on these results, tissue-specific LXR activation is a suitable therapeutic target for preventing atherosclerosis.