title: Regulation of Bcl-2 and Bcl-xL anti-apoptotic protein expression by nuclear receptor PXR in primary cultures of human and rat hepatocytes.
abstract: The pregnane X receptor (PXR) plays a major role in the protection of the body by regulating the genes involved in the metabolism and elimination of potentially toxic xeno- and endobiotics. We previously described that PXR activator dexamethasone protects hepatocytes from spontaneous apoptosis. We hypothesise a PXR-dependent co-regulation process between detoxication and programmed cell death. Using primary cultured human and rat hepatocytes, we investigated to determine if PXR is implicated in the regulation of Bcl-2 and Bcl-xL, two crucial apoptosis inhibitors. In the present study we demonstrated that the treatment of primary cultured hepatocytes with PXR agonists increased hepatocyte viability and protects them from staurosporine-induced apoptosis. The anti-apoptotic capacity of PXR activation was correlated with Bcl-2 and Bcl-xL induction at both the transcriptional and protein levels in man and rats, respectively. The inhibition of PXR expression by antisense oligonucleotide abolished PXR activators Bcl-xL induction. Accordingly, PXR overexpression in HepG2 cells led to bcl-2 induction upon clotrimazole treatment and protects cells against Fas-induced apoptosis. Our results demonstrate that PXR expression is required for Bcl-2 and Bcl-xL up-regulation upon PXR activators treatment in human and rat hepatocytes. They also suggest that PXR may protect the liver against chemicals by simultaneously regulating detoxication and the apoptotic pathway.
authors.affiliation: Laboratoire de Toxicologie Cellulaire et Moléculaire, INRA, UMR 1112, 06903 Sophia Antipolis, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Zucchini
authors.forename: Georges
authors.initials: G
authors.lastname: de Sousa
authors.forename: Béatrice
authors.initials: B
authors.lastname: Bailly-Maitre
authors.forename: Jean
authors.initials: J
authors.lastname: Gugenheim
authors.forename: Rémi
authors.initials: R
authors.lastname: Bars
authors.forename: Géraldine
authors.initials: G
authors.lastname: Lemaire
authors.forename: Roger
authors.initials: R
authors.lastname: Rahmani
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D017931:DNA Primers; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D000077297:Pregnane X Receptor; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D011987:Receptors, Steroid / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051020:bcl-X Protein
chemical_list: C494811:BCL2L1 protein, human; C494813:Bcl2l1 protein, rat; D017931:DNA Primers; D016376:Oligonucleotides, Antisense; D000077297:Pregnane X Receptor; D019253:Proto-Oncogene Proteins c-bcl-2; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D051020:bcl-X Protein