|
|
||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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.
This article has been cited by other articles:
![]() |
H. Wiersma, A. Gatti, N. Nijstad, F. Kuipers, and U. J. F. Tietge Hepatic SR-BI, not endothelial lipase, expression determines biliary cholesterol secretion in mice J. Lipid Res., August 1, 2009; 50(8): 1571 - 1580. [Abstract] [Full Text] [PDF] |
||||
![]() |
E. M. E. van Straten, N. C. A. Huijkman, J. F. W. Baller, F. Kuipers, and T. Plosch Pharmacological activation of LXR in utero directly influences ABC transporter expression and function in mice but does not affect adult cholesterol metabolism Am J Physiol Endocrinol Metab, December 1, 2008; 295(6): E1341 - E1348. [Abstract] [Full Text] [PDF] |
||||
![]() |
L. Calpe-Berdiel, N. Rotllan, C. Fievet, R. Roig, F. Blanco-Vaca, and J. C. Escola-Gil Liver X receptor-mediated activation of reverse cholesterol transport from macrophages to feces in vivo requires ABCG5/G8 J. Lipid Res., September 1, 2008; 49(9): 1904 - 1911. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. M. de Vogel-van den Bosch, N. J. W. de Wit, G. J. E. J. Hooiveld, H. Vermeulen, J. N. van der Veen, S. M. Houten, F. Kuipers, M. Muller, and R. van der Meer A cholesterol-free, high-fat diet suppresses gene expression of cholesterol transporters in murine small intestine Am J Physiol Gastrointest Liver Physiol, May 1, 2008; 294(5): G1171 - G1180. [Abstract] [Full Text] [PDF] |
||||
![]() |
Y. Liu, H. van Goor, R. Havinga, J. F. W. Baller, V. W. Bloks, F. R. van der Leij, P. J. J. Sauer, F. Kuipers, G. Navis, and M. H. de Borst Neonatal dexamethasone administration causes progressive renal damage due to induction of an early inflammatory response Am J Physiol Renal Physiol, April 1, 2008; 294(4): F768 - F776. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. N. van der Veen, R. Havinga, V. W. Bloks, A. K. Groen, and F. Kuipers Cholesterol feeding strongly reduces hepatic VLDL-triglyceride production in mice lacking the liver X receptor {alpha} J. Lipid Res., February 1, 2007; 48(2): 337 - 347. [Abstract] [Full Text] [PDF] |
||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |