The aryl hydrocarbon receptor predisposes hepatocytes to Fas-mediated apoptosis

Kyung Tae Park, Kristen A. Mitchell, Gengming Huang, Cornelis Elferink

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Liver homeostasis is achieved by the removal of diseased and damaged hepatocytes and their coordinated replacement to maintain a constant liver cell mass. Cirrhosis, viral hepatitis, and toxic drug effects can all trigger apoptosis in the liver as a means of removing the unwanted cells, and the Fas "death receptor" pathway comprises a major physiological mechanism by which this occurs. The susceptibility to Fas-mediated apoptosis is, in part, a function of the hepatocyte's proteome. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor known to influence apoptosis, conceivably by regulating the expression of genes involved in apoptotic signaling. In this article, we present evidence demonstrating that AhR expression and function promote apoptosis in liver cells in response to Fas stimulation. Reintroduction of the AhR into the AhR-negative BP8 hepatoma cells as well as into primary hepatocytes from AhR knockout mice increases the magnitude of cell death in response to Fas ligand. Enhanced apoptosis correlates with increased caspase activity and mitochondrial cytochrome c release but not with the expression of several Bcl-2 family proteins. In vivo studies showed that in contrast to wild-type mice, AhR knockout mice are protected from the lethal effects of the anti-Fas Jo2 antibody. Moreover, down-regulation of the aryl hydrocarbon receptor nuclear translocator protein in vivo by adenovirus-mediated RNA interference to suppress AhR activity provided wild-type mice partial protection from Jo2-induced lethality.

Original languageEnglish (US)
Pages (from-to)612-622
Number of pages11
JournalMolecular Pharmacology
Volume67
Issue number3
DOIs
StatePublished - Mar 2005

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Aryl Hydrocarbon Receptors
Hepatocytes
Apoptosis
Liver
Knockout Mice
Cell Death
Aryl Hydrocarbon Receptor Nuclear Translocator
CD95 Antigens
Chemical and Drug Induced Liver Injury
Death Domain Receptors
Fas Ligand Protein
Proteome
Caspases
Nuclear Proteins
RNA Interference
Cytochromes c
Adenoviridae
Hepatocellular Carcinoma
Homeostasis
Fibrosis

ASJC Scopus subject areas

  • Pharmacology

Cite this

The aryl hydrocarbon receptor predisposes hepatocytes to Fas-mediated apoptosis. / Park, Kyung Tae; Mitchell, Kristen A.; Huang, Gengming; Elferink, Cornelis.

In: Molecular Pharmacology, Vol. 67, No. 3, 03.2005, p. 612-622.

Research output: Contribution to journalArticle

Park, Kyung Tae ; Mitchell, Kristen A. ; Huang, Gengming ; Elferink, Cornelis. / The aryl hydrocarbon receptor predisposes hepatocytes to Fas-mediated apoptosis. In: Molecular Pharmacology. 2005 ; Vol. 67, No. 3. pp. 612-622.
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