Nuclear receptors as therapeutic targets in cholestatic liver diseases

Abstract

Cholestasis results in intrahepatic accumulation of cytotoxic bile acids, which cause liver damage ultimately leading to biliary fibrosis and cirrhosis. Cholestatic liver injury is counteracted by a variety of adaptive hepatoprotective mechanisms including alterations in bile acid transport, synthesis and detoxification. The underlying molecular mechanisms are mediated mainly at a transcriptional level via a complex network involving nuclear receptors including the farnesoid X receptor, pregnane X receptor, vitamin D receptor and constitutive androstane receptor, which target overlapping, although not identical, sets of genes. Because the intrinsic adaptive response to bile acids cannot fully prevent liver injury in cholestasis, therapeutic targeting of these receptors via specific and potent agonists may further enhance the hepatic defence against toxic bile acids. Activation of these receptors results in repression of bile acid synthesis, induction of phases I and II bile acid hydroxylation and conjugation and stimulation of alternative bile acid export while limiting hepatocellular bile acid import. Furthermore, the use of nuclear receptor ligands may not only influence bile acid transport and metabolism but may also directly target hepatic fibrogenesis and inflammation. Many drugs already used to treat cholestasis and its complications such as pruritus (e.g. ursodeoxycholic acid, rifampicin, fibrates) may act via activation of nuclear receptors. More specific and potent nuclear receptor ligands are currently being developed. This article will review the current knowledge on nuclear receptors and their potential role in the treatment of cholestatic liver diseases.

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

“…Bile acids, especially the tMCAs and elevated bilirubin levels in hFRGN livers will further contribute to varying extent of Fxr and Car induction in extrahepatic tissues (Huang et al, 2003;Chen et al, 2011). These translate to induction of targeted transporters and enzymes such as Mrp2, Mrp3, Mrp4 and Mdr1a, Gst4-4, Sult1a1, and Ugt1a1 (Huang et al, 2003;Zollner et al, 2006;Zollner and Trauner, 2009;Wagner et al, 2011) in hFRGN intestine, kidney or brain (Figs. 6 and Supplemental Figs.…”

Bile Acid Signaling in Metabolic Disease and Drug Therapy

“…The therapeutic potential of bile acids and derivatives for treating hepatic and biliary diseases, NAFLD, and metabolic syndrome has been extensively reviewed Fiorucci and Baldelli, 2009;Zollner and Trauner, 2009;Lian et al, 2011;Pols et al, 2011a,b;Adorini et al, 2012;Hollman et al, 2012;Stojancevic et al, 2012;McMahan et al, 2013;Mudaliar et al, 2013;Stepanov et al, 2013;Duboc et al, 2014) and will be briefly summarized. Bile acid sequestrants have long been used for treating gallstone disease.…”

Bile acids: regulation of synthesis

“…Bile acids and bile acid-activated receptors FXR, PXR, CAR, and VDR are therapeutic targets for development of drugs for treatment of gallstone, fatty liver disease, cholestatic liver disease, obesity, diabetes, and metabolic syndrome ( 12,145,146 ). A bile acid derivative, 6 ␣ -ethyl-CDCA, the rat CYP7A1 promoter, which contains the binding sites for SMAD, FoxO1, and HNF4 ␣ .…”