[PDF][PDF] Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors

TT Lu, M Makishima, JJ Repa, K Schoonjans, TA Kerr… - Molecular cell, 2000 - cell.com
TT Lu, M Makishima, JJ Repa, K Schoonjans, TA Kerr, J Auwerx, DJ Mangelsdorf
Molecular cell, 2000cell.com
The catabolism of cholesterol into bile acids is regulated by oxysterols and bile acids, which
induce or repress transcription of the pathway's rate-limiting enzyme cholesterol 7α-
hydroxylase (CYP7A1). The nuclear receptor LXRα binds oxysterols and mediates feed-
forward induction. Here, we show that repression is coordinately regulated by a triumvirate
of nuclear receptors, including the bile acid receptor, FXR; the promoter-specific activator,
LRH-1; and the promoter-specific repressor, SHP. Feedback repression of CYP7A1 is …
Abstract
The catabolism of cholesterol into bile acids is regulated by oxysterols and bile acids, which induce or repress transcription of the pathway's rate-limiting enzyme cholesterol 7α-hydroxylase (CYP7A1). The nuclear receptor LXRα binds oxysterols and mediates feed-forward induction. Here, we show that repression is coordinately regulated by a triumvirate of nuclear receptors, including the bile acid receptor, FXR; the promoter-specific activator, LRH-1; and the promoter-specific repressor, SHP. Feedback repression of CYP7A1 is accomplished by the binding of bile acids to FXR, which leads to transcription of SHP. Elevated SHP protein then inactivates LRH-1 by forming a heterodimeric complex that leads to promoter-specific repression of both CYP7A1 and SHP. These results reveal an elaborate autoregulatory cascade mediated by nuclear receptors for the maintenance of hepatic cholesterol catabolism.
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