Knight Belinda, Yeap Bu B, Yeoh George C, Olynyk John K
School of Medicine and Pharmacology, University of Western Australia, Nedlands, WA, Australia.
Carcinogenesis. 2005 Oct;26(10):1782-92. doi: 10.1093/carcin/bgi138. Epub 2005 May 25.
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.
多方面的证据表明，在慢性肝损伤的早期阶段，肝肿瘤的发生与成体肝祖（卵圆）细胞的激活和增殖有关。本研究的目的是探讨过氧化物酶体增殖物激活受体（PPARs）：PPARα、δ和γ，在介导肿瘤前疾病期间肝祖细胞行为中的作用，并研究它们作为慢性肝损伤治疗靶点的潜力。我们观察到，在小鼠开始采用胆碱缺乏、乙硫氨酸补充（CDE）致癌性肝损伤饮食模型后的前21天，随着卵圆细胞数量的增加，肝脏中PPARα和γ的表达也增加。原代和永生化肝祖细胞均表达PPARα、δ和γ，但不表达PPARγ的可变剪接形式γ2。测试了WY14643（PPARα激动剂）、GW501516（PPARδ激动剂）和吡格列酮（PPARγ激动剂）在体外调节p53永生化肝（PIL）祖细胞系行为的能力。PPARδ和γ激动剂均诱导PIL细胞剂量依赖性生长抑制和凋亡。相比之下，PPARα激动剂对PIL细胞生长没有影响。根据治疗前后肝脏基因表达模式判断，这些药物均未影响PIL细胞沿肝细胞或胆管谱系的成熟。给喂食CDE饮食14天的小鼠施用PPARγ激动剂吡格列酮，与接受安慰剂的小鼠相比，卵圆细胞反应显著减弱，纤维化程度降低。相比之下，GW501516不影响卵圆细胞数量或肝纤维化，但可抑制CDE诱导的肝脂肪变性。总之，PPARγ激动剂可减少慢性肝损伤期间的卵圆细胞增殖和纤维化，可能有助于预防肝细胞癌。
