Journal Article

Inhibition of adult liver progenitor (oval) cell growth and viability by an agonist of the peroxisome proliferator activated receptor (PPAR) family member γ, but not α or δ

Belinda Knight, Bu B. Yeap, George C. Yeoh and John K. Olynyk

in Carcinogenesis

Volume 26, issue 10, pages 1782-1792
Published in print October 2005 | ISSN: 0143-3334
Published online May 2005 | e-ISSN: 1460-2180 | DOI:
Inhibition of adult liver progenitor (oval) cell growth and viability by an agonist of the peroxisome proliferator activated receptor (PPAR) family member γ, but not α or δ

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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): PPARα, δ and γ, 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 PPARα and γ 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 PPARα, δ and γ, but not γ2, the alternate splice form of PPARγ. WY14643 (PPARα agonist), GW501516 (PPARδ agonist) and ciglitazone (PPARγ agonist) were tested for their ability to modulate the behaviour of p53-immortalized liver (PIL) progenitor cell lines in vitro. Both PPARδ and γ agonists induced dose-dependent growth inhibition and apoptosis of PIL cells. In contrast, the PPARα 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 PPARγ 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, PPARγ agonists reduce oval cell proliferation and fibrosis during chronic liver injury and may be useful in the prevention of hepatocellular carcinoma.

Keywords: CDE, choline deficient, ethionine supplemented; CK, cytokeratin; DMSO, dimethylsulphoxide; HCC, hepatocellular carcinoma; HSC, hepatic stellate cell; MTT, 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyl-tetrazolium bromide; PI, propidium iodide; PIL, p53-immortalized liver; PPAR, peroxisome proliferator activated receptor; SMA, smooth muscle actin

Journal Article.  7181 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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