Abstract 1086: Biliary Sterol Secretion is Required for Functional in vivo Reverse Cholesterol Transport
The atheroprotective effects of HDL are largely ascribed to its role in reverse cholesterol transport (RCT), viewed as transport of excess cholesterol from the periphery to the liver for subsequent excretion into feces via the bile. Recently, the intestine was shown to significantly contribute to mass excretion of neutral sterols into feces, which can be enhanced by LXR activation. The present study aimed to test the relevance of this intestinal pathway for in vivo RCT. Kinetic studies revealed counterintuitive results for a role of the intestine in RCT, namely HDL 3H-cholesteryl ether uptake by the small intestine
decreases in wild-type mice upon LXR activation by T0901317 (p<0.05),
increases in SR-BI knockout (ko) mice (p<0.05) and
decreases in Abcb4 ko mice lacking functional biliary cholesterol secretion (p<0.05).
Next, we performed in vivo RCT assays in mice using intraperitoneal injection of macrophage foam cells loaded with 3H-cholesterol. Mechanical obstruction of bile secretion by bile duct ligation almost completely abolished RCT with only trace 3H-sterol excretion into the feces (p<0.001). In a genetic model of deficient biliary cholesterol secretion (Abcb4 ko), RCT was significantly reduced (p<0.001) due to almost absent fecal 3H tracer excretion within neutral sterols (p<0.001) and reduced recovery within bile acids (p<0.05). LXR activation increased RCT in wild-type mice (p<0.001), mainly due to increased recovery of tracer within neutral sterols (p<0.001), while RCT remained unchanged in Abcb4 ko. However, mass fecal excretion of neutral sterols increased similar in response to the LXR agonist in wild-type (1.8-fold, p<0.01) and Abcb4 (1.7-fold, p<0.05) ko mice. These data demonstrate that
functional RCT depends on biliary sterol secretion, intestinal cholesterol secretion is insufficient to compensate when the biliary route is not operational,
there is no compensatory increase in RCT via bile acid synthesis when biliary cholesterol secretion is reduced,
the positive effect of LXR activation on RCT requires biliary cholesterol secretion.
These results might have important implications for treatment strategies against atherosclerotic cardiovascular disease that aim at enhancing RCT