Chapter category: Channels and Transporters
Transcriptional Regulation of Hepatobiliary Transporters
Molecular Pathogenesis of Cholestasis
Edited by: Michael Trauner and Peter JansenISBN: 0-306-48240-1
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Chapter authors:
The expression and activities of hepatobiliary transporter genes is a critical component of liver function. Both sinusoidal and canalicular membrane transporters are responsible for the coordinated transport of a wide variety of organic anions, drugs, toxins, endobiotics and bile acids that ultimately are metabolized by hepatocytes and secreted into bile. Over the past decade, a tremendous amount of new information has been uncovered regarding the molecular identification of hepatobiliary transporter genes responsible for the delivery of the principal solutes in bile, and therefore the mechanisms underlying the generation of bile. Along with the cloning and identification of critical hepatobiliary transporter genes has come the capability of exploring, and possibly modifying, the molecular mechanisms driving alterations in transporter gene expression in health and disease. Regulation at the level of mRNA transcription initiation is becoming increasingly recognized as the predominant means governing transporter gene expression. An expanding role for Hepatocyte Nuclear Factor 1a and several members of the nuclear receptor superfamily of ligand-regulatable transcription factors permits coordination of expression of multiple transporter genes. In particular, the recently-identified nuclear receptor for bile acids, FXR, serves as both sensor and effector to help maintain intracellular bile acid homeostasis. These findings have significant importance in our current understanding, and as a means of directing future therapy, of liver diseases where cholestasis is a prominent feature.
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