Lack of Abcg1 results in decreased plasma HDL cholesterol levels and increased biliary cholesterol secretion in mice fed a high cholesterol diet

Objective: The ATP Binding Cassette transporter G1 (ABCG1) has been implicated in cholesterol efflux towards HDL and reverse cholesterol transport (RCT). Biliary cholesterol secretion is considered as an important step in RCT. The aim of the present study was to determine the consequences of Abcg1 deficiency on plasma HDL, liver cholesterol metabolism and biliary cholesterol secretion under conditions of feeding either chow or a 1% cholesterol diet (HCD) or treatment with the LXR agonist T0901317. Methods and results: Abcg1 expression specifically in hepatocytes is induced by both HCD (p < 0.01) and T0901317 (p < 0.001). HCD or T0901317 treatment resulted in significantly lower plasma HDL cholesterol levels in Abcg1 knockout mice compared with controls (p < 0.05) consistent with a role of Abcg1 in cholesterol efflux towards HDL Liver lipid composition was not affected by the absence of Abcg1. Biliary cholesterol secretion was 47% higher in Abcg1(-/-) mice on HCD (p < 0.05) and not different in the chow and the T0901317 groups. The hepatic gene expression profile indicated uniformly throughout the different treatment groups decreased expression of Srebp2 and its target genes HmgCoA reductase (p < 0.05) and LDL receptor (p < 0.05) in Abcg1(-/-) mice. Conclusion: These data demonstrate that Abcg1 (i) contributes to plasma HDL cholesterol levels under conditions of dietary and pharmacological Lxr activation and (ii) might mediate, under conditions of hepatic cholesterol loading, hepatocyte cholesterol efflux towards plasma from a pool accessible for biliary secretion resulting in increased biliary cholesterol output when Abcg1 is lacking. (C) 2009 Elsevier Ireland Ltd. All rights reserved.