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

Abstract

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): PPARalpha, 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 PPARalpha 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 PPARalpha, delta and gamma, but not gamma2, the alternate splice form of PPARgamma. WY14643 (PPARalpha agonist), GW501516 (PPARdelta agonist) and ciglitazone (PPARgamma agonist) were tested for their ability to modulate the behaviour of p53-immortalized liver (PIL) progenitor cell lines in vitro. Both PPARdelta and gamma agonists induced dose-dependent growth inhibition and apoptosis of PIL cells. In contrast, the PPARalpha 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 PPARgamma 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, PPARgamma agonists reduce oval cell proliferation and fibrosis during chronic liver injury and may be useful in the prevention of hepatocellular carcinoma.

Liver X receptor α (LXRα/NR1H3) regulates differentiation of hepatocyte-like cells via reciprocal regulation of HNF4α

“…This is similar to the situation in HepaRG cells as rat oval cells are considered to be closely related to liver stem cells [36]. Inhibition of adult oval cell growth and viability has been noticed in the presence of a PPAR gamma agonist [37]. PPAR pathways as well as NR1H3, may have an important role in cellular energy metabolism during hepatogenesis.…”

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

“…20 In contrast, treating immortalized liver cells with the PPAR␤/␦ ligand GW501516 causes dosedependent growth inhibition and apoptosis. 64 Similarly, administration of GW501516 is protective against liver toxicity induced by choline deficiency, which may be due to antiinflammatory effects including inhibition of NF-B-dependent signaling and stellate cell activation. 65 Combined, these latter 2 observations are consistent with the hypothesis that ligand activation of PPAR␤/␦ could protect against liver toxicity induced by AOM and CCl 4 , as suggested from the current studies.…”

Inhibitory effect of meloxicam, a selective cyclooxygenase‐2 inhibitor, and ciglitazone, a peroxisome proliferator‐activated receptor gamma ligand, on the growth of human ovarian cancers

“…The ciglitazone group was administered ciglitazone (TOCRIS Bioscience, St. Louis, Mo) at a dose of 15 mg/kg intraperitoneally once a week until the end of the study. 30 The cisplatin group was administered cisplatin (Nippon Kayaku, Tokyo, Japan) at a dose of 5 mg/ kg intraperitoneally once on Day 0. The tumor dimensions were measured twice weekly using a vernier caliper and tumor volume was determined by external measurement according to the published method.…”