An excellent review

[Guest guest]

Br. J. Pharmacol. 156: 7-27 (2009)

Nuclear receptors as therapeutic targets in cholestatic liver

diseases.

Zollner G, Trauner M

Laboratory of Experimental and Molecular Hepatology, Division of

Gastroenterology and Hepatology, Department of Internal Medicine,

Medical University of Graz, Graz, Austria.

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. PMID: 19133988.

This is a " must read " for hepatologists. I can provide the full paper

on request.

Dave

(father of (23); PSC 07/03; UC 08/03)