Although the role of liver X receptors (LXR) in atherosclerosis is no longer questioned given their role in promoting reverse cholesterol transport (RCT) through the activation of specific genes implicated in HDL metabolism, the effect of LXR agonism on RCT remains to be investigated. Zanotti et al. tested the hypothesis that short-term administration of the LXR agonist T0901317 (T0) would have positive effects on RCT in mice. As expected, T0 produced significant increases in macrophage-derived cholesterol in the circulation and in the animals’ liver and feces. The authors also showed that these effects were likely due to the promotion of RCT via either passive diffusion of cholesterol from macrophages to HDL particles or a process mediated by class type 1 scavenger receptors. Surprisingly, lipid efflux via ABC transporters was not modified upon treatment of mice with T0. T0 also promoted the formation of larger, lipid-enriched particles, which are thought to be more capable of promoting RCT. Although it was not observed in the present study, previous studies have shown that LXR agonism causes other metabolic perturbations that increase the risk of hepatic fat deposition. This led the authors to suggest that agonism of selective LXR isoforms, such as LXRβ, might have a beneficial impact on HDL metabolism without necessarily disturbing other systems associated with lipoprotein-lipid metabolism. Further studies are needed to support this hypothesis.
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