Why are patients with liver disease jaundiced? ATP-binding cassette transporter expression in human liver disease

Abstract

Transport proteins in the basolateral and canalicular membranes of hepatocytes mediate the flux of organic solutes into and from the liver. Bile formation depends on the proper function of these transporters. Although cholestatic liver disease represents a distinct group of diseases, a certain degree of cholestasis often occurs in any kind of liver disease. To understand the molecular background of jaundice and cholestasis in human liver disease the following questions are of relevance: Is jaundice and cholestasis in human liver disease the consequence of a reduced activity of any or all of these transport proteins? If so, is this reduced activity caused by changes of transporter protein expression or by inactivation of normally expressed proteins? Are these alterations caused by changes in transcription or translation? Are cellular or humoral inflammatory mediators involved? Of particular relevance is also the question whether changes of transporter expression contribute to liver cell damage or should they be considered as adaptations protecting the liver. Experimental models to probe these questions are the bile duct ligated (BDL) rat, endotoxin- or estradiol-treated rats and mice and rats after partial hepatectomy. Ntcp mediates the sodium-dependent uptake of bile salts in the liver and Mrp2 the active hepatocanalicular secretion of organic anions into bile. Bilirubin mono- and diglucuronide, sulphated and glucuronidated bile salts, leukotriene C4 and glutathione-S-conjugates are some of the many Mrp2 substrates. Exposure of rats to endotoxin causes cholestasis with a significant decrease of Ntcp and Mrp2 mRNA and protein expression [1,2]. Down-regulation of canalicular Mrp2 is associated with an up-regulation of Mrp3 in basolateral membranes of the hepatocyte, at least in the BDL-model [3]. This may be regarded as an example of adaptation: when canalicular transport to the bile is