AUTOIMMUNE, CHOLESTATIC AND BILIARY DISEASE Stimulation of Murine Biliary Cholesterol Secretion by Thyroid Hormone is Dependent on a Functional ABCG5/G8 Complex

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, indu-ces 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 (Abcg52/2) or Lxra (Lxra2/2) and their wild-type counterparts were treated with triiodothyronine (T3) for 14 days and compared to untreated mice of corresponding genetic backgrounds. Bile was col-lected by gallbladder cannulation, and liver samples were analyzed for gene expression lev-els. Basal biliary cholesterol secretion in Abcg52/2 mice was 72 % lower than in Abcg51/1 mice. T3 treatment increased cholesterol secretion 3.1-fold in Abcg51/1 mice, whereas this response was severely blunted in Abcg52/2 mice. In contrast, biliary cholesterol secretio