Both the Peroxisome Proliferator-Activated Receptor δ Agonist, GW0742, and Ezetimibe Promote Reverse Cholesterol Transport in Mice by Reducing Intestinal Reabsorption of HDL-Derived Cholesterol

Peroxisome proliferator-activated receptor delta (PPAR delta) agonism increases HDL cholesterol and has therefore the potential to stimulate macrophage-to-feces reverse cholesterol transport (RCT). To test whether PPARd activation promotes RCT in mice, in vivo macrophage RCT was assessed using cholesterol-loaded/H-3-cholesterol-labeled macrophages injected intraperitoneally. PPARd agonist GW0742 (10 mg/kg per day) did not change H-3-tracer plasma appearance, but increased fecal H-3-free sterols excretion by 103% (p < 0.005) over 48 hours. Total free cholesterol efflux from macrophages to serum (collected from both control and GW0742 groups) was not different, although ABCA1-mediated efflux was significantly higher with GW0742. The metabolic fate of HDL labeled with H-3-cholesteryl ether or H-3-cholesteryl oleate was also measured. While H-3-cholesteryl ether tissue uptake was unchanged, the H-3-tracer recovered in fecal free sterol fraction after H-3-cholesteryl oleate injection increased by 88% with GW0742 (p < 0.0005). This was associated with a lower Niemann-Pick C1 like 1 (NPC1L1) mRNA expression in the small intestine (p < 0.05). The same experiments in mice treated with ezetimibe, which blocks NPC1L1, showed a similar 2-fold increase in fecal free sterol excretion after labeled macrophages or HDL injection. In conclusion, PPARd activation enhances excretion of macrophage or HDL-derived cholesterol in feces through reduced NPC1L1 expression in mice, comparable to the effect of ezetimibe.