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

Atherosclerosis. 2015 Dec;243(2):402-6. doi: 10.1016/j.atherosclerosis.2015.10.010. Epub 2015 Oct 8.

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.

Keywords: Atherosclerosis; Bile; Cholesterol; Liver; Macrophages; Reverse cholesterol transport.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 5
  • ATP Binding Cassette Transporter, Subfamily G, Member 8
  • ATP-Binding Cassette Transporters / deficiency
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Animals
  • Bile / metabolism*
  • Cholesterol / blood
  • Cholesterol / metabolism*
  • Feces / chemistry*
  • Gene Transfer Techniques
  • Genotype
  • Hepatobiliary Elimination*
  • Lipoproteins / deficiency
  • Lipoproteins / genetics
  • Lipoproteins / metabolism*
  • Liver / metabolism*
  • Macrophages / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Up-Regulation

Substances

  • ABCG5 protein, mouse
  • ABCG8 protein, mouse
  • ATP Binding Cassette Transporter, Subfamily G, Member 5
  • ATP Binding Cassette Transporter, Subfamily G, Member 8
  • ATP-Binding Cassette Transporters
  • Lipoproteins
  • Cholesterol