Abcg5/Abcg8-independent pathways contribute to hepatobiliary cholesterol secretion in mice

Abstract

Plö sch, Torsten, Jelske N. van der Veen, Rick Havinga, Nicolette C. A. Huijkman, Vincent W. Bloks, and Folkert Kuipers. Abcg5/Abcg8-independent pathways contribute to hepatobiliary cholesterol secretion in mice. Am J Physiol Gastrointest Liver Physiol 291: G414 -G423, 2006. First published April 13, 2006; doi:10.1152/ajpgi.00557.2005.-The ATP-binding cassette (ABC) half-transporters ABCG5 and ABCG8 heterodimerize into a functional complex that mediates the secretion of plant sterols and cholesterol by hepatocytes into bile and their apical efflux from enterocytes. We addressed the putative rate-controlling role of Abcg5/Abcg8 in hepatobiliary cholesterol excretion in mice during (maximal) stimulation of this process. Despite similar bile salt (BS) excretion rates, basal total sterol and phospholipid (PL) output rates were reduced by 82% and 35%, respectively, in chow-fed Abcg5 Ϫ/Ϫ mice compared with wild-type mice. When mice were infused with the hydrophilic BS tauroursodeoxycholate, similar relative increases in bile flow, BS output, PL output, and total sterol output were observed in wild-type, Abcg5 ϩ/Ϫ , and Abcg5 Ϫ/Ϫ mice. Maximal cholesterol and PL output rates in Abcg5 Ϫ/Ϫ mice were only 15% and 69%, respectively, of wild-type values. An infusion of increasing amounts of the hydrophobic BS taurodeoxycholate increased cholesterol excretion by 3.0-and 2.4-fold in wild-type and Abcg5 Ϫ/Ϫ mice but rapidly induced cholestasis in Abcg5 Ϫ/Ϫ mice. Treatment with the liver X receptor (LXR) agonist T0901317 increased the maximal sterol excretion capacity in wild-type mice (fourfold), concomitant with the induction of Abcg5/Abcg8 expression, but not in Abcg5 Ϫ/Ϫ mice. In a separate study, mice were fed chow containing 1% (wt/wt) cholesterol. As expected, hepatic expression of Abcg5 and Abcg8 was strongly induced (fivefold and fourfold) in wild-type but not LXR-␣-deficient (Lxra Ϫ/Ϫ ) mice. Surprisingly, hepatobiliary cholesterol excretion was increased to the same extent, i.e., 2.2-fold in wild-type mice and 2.0-fold in Lxra Ϫ/Ϫ mice, upon cholesterol feeding. Our data confirm that Abcg5, as part of the Abcg5/Abcg8 heterodimer, strongly controls hepatobiliary cholesterol secretion in mice. However, our data demonstrate that Abcg5/Abcg8 heterodimer-independent, inducible routes exist that can significantly contribute to total hepatobiliary cholesterol output.ATP-binding cassette transporter; bile formation; biliary lipids; canalicular transport MUTATIONS in the ATP binding-cassette (ABC) half-transporters ABCG5 and ABCG8 cause sitosterolemia (3, 23), which is characterized by the accumulation of plant sterols in the body (4). Data indicate that ABCG5 and ABCG8, which are highly expressed in the liver and small intestine, heterodimerize into a functional complex (3,12). Mutations in either one of the genes cause the biochemical hallmarks of the disease in humans (3, 23) as well as in mouse models (18,27). The daily intake of plant sterols, i.e., sitosterol and campesterol, from a "Western-type" diet is in the same o...

Scavenger receptor class B type I mediates biliary cholesterol secretion independent of ATP-binding cassette transporter g5/g8 in mice

“…The role of Abcg5/Abcg8 has been substantiated by showing that overexpression of these transporters results in increased biliary cholesterol secretion 19 and that knockouts for Abcg5 or Abcg8 have a decrease in biliary cholesterol secretion rates by about 75%. 18,21,26 However, there is residual biliary cholesterol secretion in Abcg5 or Abcg8 knockout mice, 18,21,26 and previous studies involving our group have shown that Abcg5/Abcg8-independent biliary cholesterol secretion occurs. [21][22][23] Based on the results of this study, we would propose that SR-BI acts as a key candidate for mediating this Abcg5/Abcg8-independent fraction of biliary cholesterol secretion.…”

“…18,21,26 However, there is residual biliary cholesterol secretion in Abcg5 or Abcg8 knockout mice, 18,21,26 and previous studies involving our group have shown that Abcg5/Abcg8-independent biliary cholesterol secretion occurs. [21][22][23] Based on the results of this study, we would propose that SR-BI acts as a key candidate for mediating this Abcg5/Abcg8-independent fraction of biliary cholesterol secretion. As evidenced by the correction of the biliary cholesterol secretion deficit of Abcg5 knockout mice by hepatic SR-BI overexpression, SR-BI can drive biliary cholesterol secretion independent of Abcg5.…”

“…19 However, in the absence of Abcb4, even high-level overexpression of Abcg5/Abcg8 does not increase biliary cholesterol secretion, 20 delineating the crucial role for biliary phospholipids in mixed micelles with bile salts as acceptors for cholesterol solubilization. Importantly, an Abcg5/Abcg8-independent cholesterol secretion pathway has been described; [21][22][23] however, the mediator of this process remains unknown.…”

Evaluation of the Contribution of the ATP Binding Cassette Transporter, P-glycoprotein, to in Vivo Cholesterol Homeostasis

“…The dimer formed by the half transporters ABCG5 and ABCG8 is the primary efflux mechanism for unmodified cholesterol from cells of the small intestine and the liver. Deletion of ABCG5 and ABCG8 does not completely ablate cholesterol efflux suggesting that a secondary mechanism for the removal of cholesterol may exist in mice 3,4 , with confirmatory findings in humans 5 .…”

Bile salt–dependent efflux of cellular phospholipids mediated by ATP binding cassette protein B4

“…18 Based on these results, it has been proposed that ABCG5 and ABCG8 require ABCB4 for the secretion of cholesterol into the bile, 18 and that Abcg5/Abcg8-independent routes can significantly contribute to total hepatobiliary cholesterol output (Ϸ20% of maximal output). 39 However, there were no data to suggest that ABCB4 is involved in the ABCG5/ABCG8-independent routes. It has been also demonstrated that biliary cholesterol excretion in Abcb4 knockout mice can be completely restored by infusion of a sufficiently hydrophobic bile salt, taurodeoxycholate, to allow solubilization of cholesterol in the absence of phospholipids, 8 and that cholesterol excretion in heterozygous Abcb4 ϩ/Ϫ mice is equal to that in wild-type mice although phospholipid excretion in these mice is 50% of normal levels.…”