Inhibition of PPARα/RXRα-mediated direct hyperplasia pathways during griseofulvin-induced hepatocarcinogenesis

Yasuyuki Nagao, Barbara A. French, Yan Cai, Samuel W. French, Yu-Jui Yvonne Wan

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Chronic griseofulvin (GF) feeding induces preneoplastic loci followed by hepatocellular carcinoma in the mouse liver. Our previous study suggested that GF-induced hepatocellular proliferation had a different mechanism from that of peroxisome proliferator (PP)-induced direct hyperplasia. The GF- induced hepatocellular proliferation was mediated through activation of immediate early genes such as Fos, Jun, Myc, and NFκB. In contrast, PP- induced direct hyperplasia does not involve activation of any of these immediate early genes. It has been shown that nuclear hormone receptors including peroxisome proliferator activated receptors (PPARs) and retinoid x receptors (RXRs) play important roles in mediating the pleiotropic effects of PPs. To examine the possible roles of PPARs and RXRs during non-PP-induced hepatocellular proliferation and the interaction between PP and non-PP- induced proliferation, we have studied the expression of the PPAR and RXR genes in the GF model using northern blot hybridizations and gel retardation assays. The data showed that the expression of PPARα and RXRα genes was down-regulated in the livers containing preneoplastic nodules and in the liver tumors induced by GF. The mRNA down-regulation was accompanied by a decrease in the amount of nuclear protein-bound to peroxisome proliferator and retinoic acid responsive elements. Down-regulation was also associated with the suppressed expression of the PPARα/RXRα target genes (i.e., acyl- Co oxidase and cytochrome P450 4A1) and the catalase gene. The RXRγ gene was also down-regulated, but the RARα, β, and γ and PPARβ and γ genes were up-regulated. These results indicated that the hepatocarcinogenesis induced by GF is accompanied by suppression of the PPARα/RXRα-mediated direct hyperplasia pathway. The differential expression of these nuclear hormone receptors reveals a new aspect for understanding the individual roles and intercommunication of PPAR, RXR, and PAR isoforms in the liver.

Original languageEnglish (US)
Pages (from-to)189-200
Number of pages12
JournalJournal of Cellular Biochemistry
Volume69
Issue number2
DOIs
StatePublished - May 1 1998

Keywords

  • Hepatocarcinoma
  • Liver hyperplasia
  • Peroxisome proliferator activated receptor
  • Retinoic acid receptor
  • Retinoid x receptor

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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