Carcinogenesis Advance Access published online on May 25, 2005
Carcinogenesis, doi:10.1093/carcin/bgi138
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1 School of Medicine and Pharmacology, Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia; Western Australian Institute for Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia
* To whom correspondence should be addressed. 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
Received March 1, 2005
Revised May 13, 2005
Accepted May 19, 2005
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
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
2 School of Biomedical and Chemical Sciences, Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia; Western Australian Institute for Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia
3 School of Medicine and Pharmacology, Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia; Western Australian Institute for Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia; Department of Gastroenterology, Fremantle Hospital, Fremantle, Western Australia
Belinda Knight, E-mail: belindat{at}cyllene.uwa.edu.au
Abstract 
, 
and 
, 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 and 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 immortalised liver progenitor cells were found to express PPAR, and , but not 2, the alternate splice form of PPAR. WY14643 (PPAR agonist), GW501516 (PPAR agonist) and ciglitazone (PPAR agonist) were tested for their ability to modulate the behaviour of p53 immortalised liver progenitor (PIL) cell lines in vitro. Both PPAR and agonists induced dose-dependant growth inhibition and apoptosis of PIL cells. In contrast, the PPAR 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 agonist ciglitazone to mice fed the CDE diet for 14 days resulted in a significantly diminished oval cell response, and decreased fibrosis compared to those receiving placebo. In contrast, GW501516 did not affect oval cell numbers of liver fibrosis, but inhibited CDE-induced hepatic steatosis. In summary, PPAR 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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