Autoimmune, Cholestatic and Biliary Disease
Article first published online: 14 OCT 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 5, pages 1828–1837, November 2012
How to Cite
Bonde, Y., Plösch, T., Kuipers, F., Angelin, B. and Rudling, M. (2012), Stimulation of murine biliary cholesterol secretion by thyroid hormone is dependent on a functional ABCG5/G8 complex. Hepatology, 56: 1828–1837. doi: 10.1002/hep.25861
Potential conflict of interest: Dr. Angelin advises and received grants from Karo Bio. Dr. Rudling received grants from Karo Bio.
This work was supported by grants from the Swedish Research Council, the Grönberg and the Swedish Heart-Lung Foundations, the Foundation of Old Female Servants, Stockholm County Council (ALF), the Dutch Heart Foundation, the Cardiovascular Program, the Karolinska Institute/Stockholm City Council, and the Karolinska Institute.
- Issue published online: 31 OCT 2012
- Article first published online: 14 OCT 2012
- Accepted manuscript online: 24 JUL 2012 10:03AM EST
- Manuscript Accepted: 15 MAY 2012
- Manuscript Received: 9 JAN 2012
Secretion of cholesterol into bile is important for the elimination of cholesterol from the body. Thyroid hormone (TH) increases biliary cholesterol secretion and hepatic gene expression of adenosine triphosphate (ATP)-binding cassette, subfamily G (WHITE), member 5 (ABCG5) and ATP-binding cassette, subfamily G (WHITE), member 8 (ABCG8), two half-transporters that act as a heterodimeric complex promoting sterol secretion. In addition, nuclear liver x receptor-alpha (LXRa), also regulated by TH, induces gene expression of ABCG5/G8. We here investigated if the TH-induced stimulation of biliary cholesterol secretion is mediated by the ABCG5/G8 complex in vivo, and if so, whether LXRa is involved. Mice homozygous for disruption of Abcg5 (Abcg5−/−) or Lxra (Lxra−/−) and their wild-type counterparts were treated with triiodothyronine (T3) for 14 days and compared to untreated mice of corresponding genetic backgrounds. Bile was collected by gallbladder cannulation, and liver samples were analyzed for gene expression levels. Basal biliary cholesterol secretion in Abcg5−/− mice was 72% lower than in Abcg5+/+ mice. T3 treatment increased cholesterol secretion 3.1-fold in Abcg5+/+ mice, whereas this response was severely blunted in Abcg5−/− mice. In contrast, biliary cholesterol secretion in T3-treated Lxra+/+ and Lxra−/− mice was increased 3.5- and 2.6-fold, respectively, and did not differ significantly. Conclusions: TH-induced secretion of cholesterol into bile is largely dependent on an intact ABCG5/G8 transporter complex, whereas LXRa is not critical for this effect. (HEPATOLOGY 2012;56:1828–1837)