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Carcinogenesis Advance Access originally published online on May 25, 2005
Carcinogenesis 2005 26(10):1782-1792; doi:10.1093/carcin/bgi138
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Carcinogenesis vol.26 no.10 © Oxford University Press 2005; all rights reserved.

Inhibition of adult liver progenitor (oval) cell growth and viability by an agonist of the peroxisome proliferator activated receptor (PPAR) family member {gamma}, but not {alpha} or {delta}

Belinda Knight 1, 3, *, Bu B. Yeap 1, 3, George C. Yeoh 2, 3 and John K. Olynyk 1, 3, 4

1 School of Medicine and Pharmacology, 2 School of Biomedical and Chemical Sciences, 3 Western Australian Institute for Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia and 4 Department of Gastroenterology, Fremantle Hospital, Fremantle, WA, Australia

* To whom correspondence should be addressed at: School of Medicine and Pharmacology, Fremantle Hospital, Alma Road, Fremantle, WA 6160, Australia Email: belindat{at}cyllene.uwa.edu.au

Multifaceted evidence links the development of liver tumours to the activation and proliferation of adult liver progenitor (oval) cells during the early stages of chronic liver injury. The aim of this study was to examine the role of the peroxisome proliferator activated receptors (PPARs): PPAR{alpha}, {delta} and {gamma}, in mediating the behaviour of liver progenitor cells during pre-neoplastic disease and to investigate their potential as therapeutic targets for the treatment of chronic liver injury. We observed increased liver expression of PPAR{alpha} and {gamma} in concert with expanding oval cell numbers during the first 21 days following commencement of the choline deficient, ethionine supplemented (CDE) dietary model of carcinogenic liver injury in mice. Both primary and immortalized liver progenitor cells were found to express PPAR{alpha}, {delta} and {gamma}, but not {gamma}2, the alternate splice form of PPAR{gamma}. WY14643 (PPAR{alpha} agonist), GW501516 (PPAR{delta} agonist) and ciglitazone (PPAR{gamma} agonist) were tested for their ability to modulate the behaviour of p53-immortalized liver (PIL) progenitor cell lines in vitro. Both PPAR{delta} and {gamma} agonists induced dose-dependent growth inhibition and apoptosis of PIL cells. In contrast, the PPAR{alpha} agonist had no effect on PIL cell growth. None of the drugs affected the maturation of PIL cells along either the hepatocytic or biliary lineages, as judged by their patterns of hepatic gene expression prior to and following treatment. Administration of the PPAR{gamma} agonist ciglitazone to mice fed with the CDE diet for 14 days resulted in a significantly diminished oval cell response and decreased fibrosis compared with those receiving placebo. In contrast, GW501516 did not affect oval cell numbers or liver fibrosis, but inhibited CDE-induced hepatic steatosis. In summary, PPAR{gamma} agonists reduce oval cell proliferation and fibrosis during chronic liver injury and may be useful in the prevention of hepatocellular carcinoma.


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