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1 Center for Liver, Digestive and Metabolic Diseases, Laboratory of Pediatrics, University Medical Center Groningen, Groningen, Netherlands
2 Laboratory of Pediatrics, University Medical Center Groningen, Center for Liver, Digestive and Metabolic Disease, 9713 EZ Groningen, United States
* To whom correspondence should be addressed. E-mail: t.ploesch{at}med.umcg.nl.
The ABC half-transporters ABCG5 and ABCG8 heterodimerize into a functional complex that mediates hepatobiliary sterol secretion. We have addressed the putative rate-controlling role of Abcg5/Abcg8 in mice during stimulation of this process. Despite similar bile salt (BS) excretion rates, basal total sterol and phospholipid (PL) output was reduced by 82 % and 35 %, respectively, in Abcg5-/- mice. Upon infusion with the hydrophilic bile salt TUDCA, similar relative increases in bile flow, BS output, PL output and total sterol output were observed in wild-type, Abcg5+/- and Abcg5-/- mice. Maximal cholesterol and PL output rates in Abcg5-/- mice were only 15 % and 69 %, respectively, of wild-type values. Infusion of increasing amounts of the hydrophobic bile salt TDCA increased cholesterol excretion 3.0- and 2.4-fold in wild-type and Abcg5-/- mice, but rapidly induced cholestasis in Abcg5-/- mice. Treatment with the LXR agonist T0901317 increased the maximal sterol excretion capacity in wild-type mice (4-fold), concomitant with induction of Abcg5/Abcg8 expression, but not in Abcg5-/- mice. In a separate study, mice were fed chow containing 1% cholesterol. As expected, hepatic expression of Abcg5/Abcg8 was strongly induced (4-fold) in wild-type but not in liver x-receptor alpha-deficient (Lxra-/-) mice. Surprisingly, hepatobiliary cholesterol excretion was increased to the same extent, i.e., 2.2-fold in wild-type and 2.0-fold in Lxra-/- mice, upon cholesterol-feeding. Our data confirm that Abcg5, as part of the Abcg5/Abcg8 heterodimer, strongly controls hepatobiliary cholesterol secretion in mice. However, we demonstrate that Abcg5/Abcg8-independent, inducible routes exist that can significantly contribute to total hepatobiliary cholesterol output.
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