New molecular insights into the mechanisms of cholestasis☆

Recent progress in basic research has enhanced our understanding of the molecular mechanisms of normal bile secretion and their alterations in cholestasis. Genetic transporter variants contribute to an entire spectrum of cholestatic liver diseases and can cause hereditary cholestatic syndromes or determine susceptibility and disease progression in acquired cholestatic disorders. Cholestasis is associated with complex transcriptional and post-transcriptional alterations of hepatobiliary transporters and enzymes participating in bile formation. Ligand-activated nuclear receptors for bile acids and other biliary compounds play a key role in the regulation of genes required for bile formation. Pharmacological interventions in cholestasis may aim at modulating such novel regulatory pathways. This review will summarize the principles of molecular alterations in cholestasis and will give an overview of potential clinical implications.

Abbreviations: ABC, ATP-binding cassette, BSEP, bile salt export pump, BRIC, benign recurrent intrahepatic cholestasis, CAR (NR1I3), constitutive androstane receptor, CBDL, common bile duct ligation, CYP, cytochrome p450, FXR (NR1H4), farnesoid X receptor/bile acid receptor, HNF, hepatocyte nuclear factor, ICP, intrahepatic cholestasis of pregnancy, LPS, lipopolysaccharide, MDR, multidrug resistance gene, MRP, multidrug resistance-associated protein, NTCP (SLC10A1), Na⁺/taurocholate cotransporter, OATP (SLC21A), organic anion transporter, OST, organic solute transporter, PBC, primary biliary cirrhosis, PFIC, progressive familial intrahepatic cholestasis, PSC, primary sclerosing cholangitis, PXR (NR1I2), pregnane X receptor, RARα (NR1B1), retinoic acid receptor, RXRα (NR2B1), retinoid X receptor, SHP (NR0B2), short heterodimer partner, TNFα, tumor necrosis factor alpha

Keywords: Cholestasis, Bile acids, Hepatobiliary transporters, Nuclear receptors