Nuclear receptor ligands in therapy of cholestatic liver disease.

Cholestasis is a clinical syndrome resulting from disturbed bile formation. The etiology includes different diseases ranging from genetic defects in hepatocellular bile formation to inflammatory diseases of the bile ducts. Many cholestatic diseases are progressive and ultimately fatal. Whatever the cause, cholestasis results in intrahepatic accumulation of cytotoxic bile acids which lead to liver injury reflected by disruption of hepatocellular integrity, inflammation, fibrosis, cirrhosis and increased risk for development of cancer. Determinants of bile secretion undergo an adaptive response during cholestasis aiming to minimize hepatic injury. This adaptation occurs by modification of transport and metabolism of bile acids and other organic solutes in liver, kidney and intestine. The underlying molecular mechanisms are mediated mainly at a transcriptional level by a complex network involving ligand-activated nuclear receptors. However, the adaptive response to accumulation of bile acids cannot fully prevent or repair liver injury in cholestasis. Therefore, novel therapeutic strategies have to be developed involving nuclear receptor ligands which may intensify the protection of the hepatobiliary system in cholestatic disease.