The ATP-binding cassette transporter ABCB4/MDR3 is critical for biliary 
phosphatidylcholine (PC) excretion at the canalicular membrane of hepatocytes. 
Defective ABCB4 gene expression and protein function result in various 
cholestatic liver and bile duct injuries. Thyroid hormone receptor (THR) is a 
major regulator of hepatic lipid metabolism; we explored its potential role in 
ABCB4 regulation. Thyroid hormone T3 stimulation to human hepatocyte models 
showed direct transcriptional activation of ABCB4 in a dose- and time-dependent 
manner. To determine whether THRβ1 (the main THR isoform of the liver) is 
involved in regulation, we tested THRβ1-specific agonists (e.g., GC-1, KB-141); 
these agonists resulted in greater stimulation than the native hormone. KB-141 
activated hepatic ABCB44 expression in mice, which enhanced biliary PC secretion 
in vivo. We also identified THR response elements 6 kb upstream of the ABCB4 
locus that were conserved in humans and mice. Thus, T3-via THRβ1 as a novel 
transcriptional activator regulates ABCB4 to increase ABCB4 protein levels at 
the canalicular membrane and promote PC secretion into bile. These findings may 
have important implications for understanding thyroid hormone function as a 
potential modifier of bile duct homeostasis and provide pharmacologic 
opportunities to improve liver function in hepatobiliary diseases caused by low 
ABCB4 expression.