Reverse cholesterol transport was assessed following the intraperitoneal injection of?[3H]-cholesterol-labelled J774 macrophages to hypercholesterolemic apoE- and apoE/CD36 double-deficient mice that had been treated for 12 weeks with EP 80317. Forty-eight hours after the administration of [3H]-cholesterol-labelled cells, blood, liver, intestines and feces were harvested. The radioactivity recovered in the feces (cholesterol and bile acid combined) was significantly increased by 311 % (P?=?0.0259) in EP 80317-treated mice compared with that found in vehicle-treated mice despite no significant change in [3H]-tracer recovery in plasma between groups. Whereas the mRNA levels of LXR¦Á in the gut were significantly upregulated, mRNA and protein levels of the Niemann-Pick C1-like 1 protein (NPC1L1) transporter, a LXR¦Á target which regulates intestinal cholesterol absorption, were downregulated in EP 80317-treated mice. In contrast, neither mRNA nor protein levels of investigated transporters and receptors were modulated in the small intestine of double-deficient mice, nor was the fecal recovery of radioactivity. No change was observed in targeted genes in liver of either apoE- or apoE/CD36 double-deficient mice after a chronic treatment with EP 80317.
This study shows that EP 80317 elicits macrophage-to-feces reverse cholesterol transport in a manner dependent on CD36 expression. This effect is associated with the upregulation of LXR¦Á and the downregulation of NPC1L1 expression.