Trends in Molecular Medicine
Molecular aspects of bile formation and cholestasis
Section snippets
Basic concepts of bile formation
Bile formation results from the active secretion of osmotically active compounds by hepatocytes into the canalicular space, followed by the passive movement of water through the tight junctions. Bile salts are the main solutes in bile and are considered to be the major osmotic driving force in the generation of bile flow, although BS-independent processes also contribute to bile production 1, 8. Transport of biliary constituents from blood to bile is a vectorial process that includes uptake
Molecular basis of hepatobiliary transport
The main membrane transporters that primarily determine hepatic bile production are now largely characterized at the molecular level. Most of them have been cloned from both human and rodent tissues. Information on the localization, nomenclature and function of hepatobiliary transporters is listed in Table 1. Some of these transporters are also expressed in tissues other than the liver, where they play specific physiological roles. Owing to space limitations, only the basic concepts of hepatic
Molecular mechanisms in cholestasis
Cholestasis is defined as the impairment of normal bile flow resulting either from a functional defect at the level of the hepatocyte or from obstruction at the bile duct level. Cholestasis can result from infections, the use of certain drugs, and autoimmune, metabolic or genetic disorders [21]. Identification of the transport proteins involved in bile formation led to the concept that altered expression and/or function of membrane transporters might underlie some forms of cholestasis.
Therapeutic perspectives
Treatment options for cholestatic diseases are limited [54]. Stimulation of defective transporter expression and function might be of therapeutic benefit in cholestasis. Treatment strategies could also be directed to support and stimulate rescue pathways such as alternative detoxification and elimination routes.
The anti-cholestatic drug ursodeoxycholic acid (UDCA) acts, at least in part, by stimulation of transporter expression or function [55]. UDCA stimulates vesicular exocytosis and
Concluding remarks
Recent insights into the mechanisms of bile formation have established that this function of the liver depends of a concerted action of membrane transporters. Molecular regulation of these hepatobiliary transport systems in cholestasis seems to be part of an adaptive response aiming to minimize the extent of cholestatic injury. A better understanding of the molecular mechanisms involved in cholestasis, particularly the role of NHRs in transcriptional regulation of hepatic transporter
Acknowledgements
This work was supported by grants from the Fondo Nacional de Ciencia y Tecnologı́a (FONDECYT Grant No. 1020641 to M.A.), the Jubilee Funds of the Austrian National Bank (Grant No. 10266 to M.T.), and the Austrian Science Foundation (Grant No. P15502 to M.T.). We apologize to the authors of numerous primary references whose work could not be cited owing to space limitations.
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