Carcinogenesis, Vol 19, 43-48, Copyright © 1998 by Oxford University Press
RA Roberts, NH James, NJ Woodyatt, N Macdonald and JD Tugwood
Peroxisome proliferators (PPs) are a class of nongenotoxic rodent
hepatocarcinogens. We have demonstrated previously that PPs suppress both
spontaneous rat hepatocyte apoptosis and that induced by exogenous stimuli
such as transforming growth factor-beta1 (TGFbeta1). PPs transcriptionally
activate the peroxisome proliferator activated receptor-alpha (PPAR alpha),
a member of the nuclear hormone receptor superfamily. Here, we investigate
whether activation of PPAR alpha mediates the suppression of rat hepatocyte
apoptosis induced by PPs. We isolated a naturally occurring variant form of
PPAR alpha (hPPAR alpha- 6/29) from human liver by PCR cloning.
Electrophoretic mobility shift assays (EMSA) demonstrated that hPPAR
alpha-6/29 shared the ability of mPPAR alpha to heterodimerise with the
retinoid X receptor (RXR) and bind to DNA. When hPPAR alpha-6/29 was
transfected into Hepa1c1c7 cells together with a reporter plasmid
containing a PPAR response element (PPRE), hPPAR alpha-6/29, unlike mPPAR
alpha, could not be activated by PPs. Furthermore, hPPAR alpha-6/29 could
act as a dominant negative regulator of PPAR-mediated gene transcription
since increasing concentrations of hPPAR alpha-6/29 abrogated the
activation of co- transfected mPPAR alpha. When introduced into primary rat
liver cell cultures by transient transfection, hPPAR alpha-6/29 prevented
the suppression of hepatocyte apoptosis by the PP nafenopin, but not that
seen in response to phenobarbitone (PB), a nongenotoxic carcinogen whose
action does not involve PPAR alpha. The suppression of hepatocyte apoptosis
was abrogated completely even though only 30% of hepatocytes were
transfected, suggesting the involvement of a soluble factor. These data
indicate that activation of rat liver PPAR alpha provides a survival signal
for hepatocytes, preventing their death in response to apoptotic stimuli.
ARTICLES
Evidence for the suppression of apoptosis by the peroxisome proliferator activated receptor alpha (PPAR alpha)
Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, UK. ruth.roberts@CTL.ZENECA.com
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