Developmental changes in HuR and TTP protein abundance correlated with previously EPZ-6438 cost characterized ontogenic changes in rat ileal and renal ASBT expression. These studies not only show that ASBT expression is controlled at the level of mRNA stability by way of its 3′UTR, but also identify HuR and TTP as two key transacting factors that are involved in exerting counterregulatory effects on ASBT mRNA stability. (HEPATOLOGY 2011;) The apical sodium-dependent bile acid transporter (ASBT) is the major carrier protein involved in the ileal reabsorption of bile acids.1, 2 ASBT also transports bile acids across the apical membrane of renal proximal

convoluted tubule cells and cholangiocytes. Ileal transport plays a critical role in the enterohepatic circulation of bile salts. Bile acids are essential for normal liver function, in particular for maintenance of bile flow. In addition, they are essential for intestinal absorption of fat and fat-soluble vitamins. ASBT-mediated Fulvestrant ileal bile acid

transport leads to physiologically relevant signaling to the gallbladder and liver by way of ileal secretion of fibroblast growth factor-19.3, 4 Both deficiency and surplus of bile acids can lead to liver-based pathologic processes. As such, a number of mechanisms exist permitting tight regulation of bile acid homeostasis, thereby preventing disease.5 The regulation of ASBT expression is complex and has been the subject of many recent investigations. Mechanisms of transcriptional control of ASBT expression much have been elucidated over the past 10 years.1 More recent studies have implicated posttranscriptional processes in regulating ASBT expression.6-8 Normal ontogeny of ileal ASBT expression in the rat is biphasic, with fetal expression, postnatal repression, and induction at weaning.9 Postnatal repression of ASBT expression may provide a critical signal to enhance hepatic synthesis

of bile acids, thereby expanding the bile acid pool size. Descriptive analyses of the ontogeny of ASBT in rat ileum and kidney suggest that ASBT expression may be controlled in part by regulated changes in mRNA stability.10, 11 During normal development in the rat ileum there is a greater than 100-fold increase in steady-state ASBT messenger RNA (mRNA) levels, whereas there is only a 10-fold difference in ASBT transcription as assessed by nuclear run-on assays.10, 11 In preweaning, kidney steady-state ASBT mRNA levels are 10-fold higher than in the ileum, yet transcription rates are similar. These findings suggest that mRNA stabilization contributes to the steady-state accumulation of ASBT mRNA in the adult ileum. Moreover, they also support that differential stabilization of ASBT mRNA plays a critical role in controlling ASBT expression in a tissue-specific manner. Currently, there are no data that describe a molecular mechanism for the regulation of ASBT expression by way of changes in mRNA stability and thus the following investigations were undertaken.