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

• Published in: Atherosclerosis Vol. 243; no. 2; pp. 402 - 406
• Main Authors: Dikkers, Arne, de Boer, Jan Freark, Groen, Albert K, Tietge, Uwe J.F
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01.12.2015
• Subjects: Animals; Atherosclerosis; ATP Binding Cassette Transporter, Sub-Family G, Member 5; ATP Binding Cassette Transporter, Sub-Family G, Member 8; ATP-Binding Cassette Transporters - deficiency; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Bile; Bile - metabolism; Bile - secretion; Cardiovascular; Cholesterol; Cholesterol - blood; Cholesterol - metabolism; Cholesterol - secretion; Feces - chemistry; Gene Transfer Techniques; Genotype; Hepatobiliary Elimination; Lipoproteins - deficiency; Lipoproteins - genetics; Lipoproteins - metabolism; Liver; Liver - metabolism; Liver - secretion; Macrophages; Macrophages - metabolism; Macrophages - secretion; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Reverse cholesterol transport; Up-Regulation; Macrophages; Liver; Cholesterol; Reverse cholesterol transport; Atherosclerosis; Bile
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2015.10.010

Abstract 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.