Secretion of bile is an important excretory route for a wide range of endogenous and exogenous compounds, also known as endobiotics (e.g., bile acids, bilirubin, cholesterol, phospholipids) and xenobiotics (e.g., drugs and their metabolites), which may become toxic when accumulating in the liver [1–3]. Bile acids, the major component of bile, are not only essential for the digestion and absorption of lipids from the intestinal lumen, but also have multiple endocrine functions as regulators of hepatic glucose and lipid metabolism, liver regeneration, inflammation, and intestinal bacterial flora . Cholestasis is an impairment of bile secretion which is typically characterized by reduced bile flow and retention of biliary constituents (normally secreted into bile) in blood, liver, as well as extrahepatic organs and tissues . Histopathologically, cholestasis is characterized by bilirubinostasis with bile plugs and cholate-stasis with feathery degeneration of (mainly periportal) hepatocytes . An excellent, generally applicable definition of cholestasis, irrespective of the cause and etiology, has been coined by Serge Erlinger describing this condition as “failure of bile to reach the duodenum in sufficient amounts” .
Bile Acid Cystic Fibrosis Transmembrane Conductance Regulator Bile Salt Export Pump Cystic Fibrosis Transmembrane Conductance Regulator Gene Cholestatic Injury
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This work was supported by grants P18613-B05, P19118-B05 and F3008-B05 (to M.T.) from the Austrian Science Foundation and a GENAU project grant from the Austrian Ministry of Science.
Hofmann AF. The enterohepatic circulation of bile acids in mammals: form and functions. Front Biosci. 2009;14:2584–98.PubMedCrossRefGoogle Scholar
Trauner M, Boyer JL. Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev. 2003;83:633–71.PubMedGoogle Scholar
Zollner G, Marschall HU, Wagner M, Trauner M. Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations. Mol Pharm. 2006;3:231–51.PubMedCrossRefGoogle Scholar
Fickert P, Zollner G, Fuchsbichler A, Stumptner C, Weiglein AH, Lammert F, et al. Ursodeoxycholic acid aggravates bile infarcts in bile duct-ligated and Mdr2 knockout mice via disruption of cholangioles. Gastroenterology. 2002;123:1238–51.PubMedCrossRefGoogle Scholar
Fickert P, Fuchsbichler A, Wagner M, Zollner G, Kaser A, Tilg H, et al. Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology. 2004;127:261–74.PubMedCrossRefGoogle Scholar
Jacquemin E, de Vree JM, Cresteil D, Sokal EM, Sturm E, Dumont M, et al. The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. Gastroenterology. 2001;120:1448–58.PubMedCrossRefGoogle Scholar
Jacquemin E. Role of multidrug resistance 3 deficiency in pediatric and adult liver disease: one gene for three diseases. Semin Liver Dis. 2001;21:551–62.PubMedCrossRefGoogle Scholar
Balistreri WF. Inborn errors of bile acid biosynthesis and transport. Novel forms of metabolic liver disease. Gastroenterol Clin North Am. 1999;28:145–72, vii.Google Scholar
Stieger B, Fattinger K, Madon J, Kullak-Ublick GA, Meier PJ. Drug- and estrogen-induced cholestasis trough inhibition of the paepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology. 2000;118:422–30.PubMedCrossRefGoogle Scholar
Keitel V, Burdelski M, Vojnisek Z, Schmitt L, Häussinger D, Kubitz R. De novo bile salt transporter antibodies as a possible cause of recurrent graft failure after liver transplantation: a novel mechanism of cholestasis. Hepatology. 2009;50:510–7.PubMedCrossRefGoogle Scholar
Zollner G, Fickert P, Zenz R, Fuchsbichler A, Stumptner C, Kenner L, et al. Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases. Hepatology. 2001;33:633–46.PubMedCrossRefGoogle Scholar
Zollner G, Fickert P, Silbert D, Fuchsbichler A, Marschall HU, Zatloukal K, et al. Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol. 2003;38:717–27.PubMedCrossRefGoogle Scholar
Zollner G, Wagner M, Fickert P, Silbert D, Gumhold J, Zatloukal K, et al. Expression of bile acid synthesis and detoxification enzymes and the alternative bile acid efflux pump MRP4 in patients with primary biliary cirrhosis. Liver Int. 2007;27:920–9.PubMedCrossRefGoogle Scholar
Banales JM, Prieto J, Medina JF. Cholangiocyte anion exchange and biliary bicarbonate excretion. World J Gastroenterol. 2006;12:3496–511.PubMedGoogle Scholar
Fickert P, Trauner M. When lightning strikes twice: the plot thickens for a dual role of the anion exchanger 2 (AE2/SLC4A2) in the pathogenesis and treatment of primary biliary cirrhosis. J Hepatol. 2009;50:633–5.PubMedCrossRefGoogle Scholar
Salas JT, Banales JM, Sarvide S, Recalde S, Ferrer A, Uriarte I. Oude Elferink RP, Prieto J, Medina JF. Ae2a, b-deficient mice develop antimitochondrial antibodies and other features resembling primary biliary cirrhosis. Gastroenterology. 2008;134:1482–93.PubMedCrossRefGoogle Scholar
Phillips MJ, Poucell S, Oda M. Mechanisms of cholestasis. Lab Invest. 1986;54:593–608.PubMedGoogle Scholar
Trauner M, Wagner M, Fickert P, Zollner G. Molecular regulation of hepatobiliary transport systems: clinical implications for understanding and treating cholestasis. J Clin Gastroenterol. 2005;39 Suppl 2:S111–24.PubMedCrossRefGoogle Scholar