[Molecular mechanisms of bile formation and cholestatic diseases].

Biliary function is a vital function of the liver which results from the vectorial transport of endogenous and exogenous substrates through three compartments sequentially: the vascular space, the cellular space and the biliary space. The biliary function is responsible for the homeostasis of lipid metabolism in particular of cholesterol metabolism, the elimination of toxic endo--and xenobiotics such as (bilirubin, lipid bacteria products (endotoxin)) and several inflammatory mediators. Bile elaborated in canaliculi, is modified by cholangiocytes through secretion and absorption. Bile is essential for the intestinal digestion and absorption of nutriments. The main determinant of bile formation is an osmotic filtration process resulting from active transport of bile acids and other osmotic solutes (glutathione). Most of the membrane transporters ensuring bile formation have now been identified. The expression of these membrane transporters is regulated through transcriptional and post-tranductional mechanisms. Transcriptional regulation is under the control of nuclear receptors activated by ligands such as bile acids, which act as endogenous steroids synthesized from cholesterol in hepatocytes. Cholestatic liver diseases comprise genetic diseases resulting from the complex interaction between genetic and environmental factors. Monogenic cholestatic diseases recently identified illustrate the key role of membrane transporters in biliary function. Bile acids and inflammatory mediators are potent modulators transporters and nuclear receptor genes and thus trigger an adaptative response to cholestasis. The extent of this adaptative response could explain the compelling phenotypic variability of cholestatic diseases in childhood and adults. The firstline medical treatment is currently ursodeoxycholic acid and in case of failure of this medical treatment, liver transplantation is required. Recent progress in the molecular pathogenesis of bile formation and cholestatic liver diseases is expected to provide the design of drugs targeted to the molecular abnormalities typical of cholestatic diseases.