Hepatic ABCG5/G8 overexpression substantially increases biliary cholesterol secretion but does not impact in vivo macrophage-to-feces RCT

Background and aims: Biliary cholesterol secretion is important for reverse cholesterol transport (RCT). ABCG5/G8 contribute most cholesterol mass secretion into bile. We investigated the impact of hepatic ABCG5/G8 on cholesterol metabolism and RCT.

Methods: Biliary and fecal sterol excretion (FSE) as well as RCT were determined using wild-type controls, Abcg8 knockout mice, Abcg8 knockouts with adenovirus-mediated hepatocyte-specific Abcg8 reinstitution and hepatic Abcg5/g8 overexpression in wild-types.

Results: In Abcg8 knockouts, biliary cholesterol secretion was decreased by 75% (p <0.001), while mass FSE and RCT were unchanged. Hepatic reinstitution of Abcg8 increased biliary cholesterol secretion 5-fold (p <0.001) without changing FSE or overall RCT. Overexpression of both ABCG5/G8 elevated biliary cholesterol secretion 5-fold and doubled FSE (p <0.001) without affecting overall RCT.

Conclusions: ABCG5/G8 mediate mass biliary cholesterol secretion but not from a RCT-relevant pool. Intervention strategies aiming at increasing hepatic Abcg5/g8 expression for enhancing RCT are not likely to be successful. (C) 2015 Elsevier Ireland Ltd. All rights reserved.