Modulation of hepatocyte apoptosis: Cross-talk between bile acids and nuclear steroid receptors

S. Solá, J. D. Amaral, M. M. Aranha, C. J. Steer, C. M.P. Rodrigues

Research output: Contribution to journalReview articlepeer-review

24 Scopus citations

Abstract

The efficient removal of unwanted cells, such as senescent, damaged, mutated or infected cells is crucial for the maintenance of normal liver function. In fact, apoptosis has emerged as a potential contributor to the pathogenesis of a number of hepatic disorders, such as viral hepatitis, autoimmune diseases, ethanol-induced injury, cholestasis, and hepatocellular carcinoma. In contrast to the effect of cytotoxic bile acids in the liver, ursodeoxycholic acid (UDCA) has increasingly been used for the treatment of various liver disorders. The clinical efficacy of this hydrophilic bile acid was first recognized by its use in traditional Asian medicine. However, many studies have subsequently confirmed that UDCA improves liver function by three major mechanisms of action, including protection of cholangiocytes against the cytotoxicity of hydrophobic bile acids, stimulation of hepatobiliary secretion, and inhibition of liver cell apoptosis. UDCA acts as a potent inhibitor of the classical mitochondrial pathway of apoptosis, but also interferes with alternate and upstream molecular targets such as the E2F-1/p53 pathway. Together, there is growing evidence that this hydrophilic bile acid may modulate gene expression to prevent cell death. Curiously, as a cholesterol-derived molecule, UDCA interacts with nuclear steroid receptors, such as the glucocorticoid receptor. Nuclear steroid receptors play crucial roles in mediating steroid hormone signaling involved in many biological processes, including apoptosis. Here, we review the anti-apoptotic mechanisms of UDCA in hepatic cells, and discuss a potential involvement of nuclear steroid receptors in mediating the survival effects of UDCA.

Original languageEnglish (US)
Pages (from-to)3039-3051
Number of pages13
JournalCurrent medicinal chemistry
Volume13
Issue number25
DOIs
StatePublished - Oct 2006

Keywords

  • Apoptosis
  • Bc1-2 family
  • Bile acids
  • E2F/p53
  • Liver
  • Nuclear steroid receptors
  • Nuclear trafficking
  • TGF-β1

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