Critical role for transcription coactivator Peroxisome Proliferator- activated Receptor (PPAR)-binding protein/TRAP220 in liver regeneration and PPARα ligand-induced liver tumor development

Kojiro Matsumoto, Songtao Yu, Yuzhi Jia, Mohamed R. Ahmed, Navin Viswakarma, Joy Sarkar, Papreddy V. Kashireddy, M. Sambasiva Rao, William Karpus, Frank J. Gonzalez, Janardan K. Reddy*

*Corresponding author for this work

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Disruption of the gene encoding for the transcription coactivator peroxisome proliferator-activated receptor (PPAR)-binding protein (PBP/TRAP220/DRIP205/Med1) in the mouse results in embryonic lethality. Here, we have reported that targeted disruption of the Pbp/Pparbp gene in hepatocytes (PbpΔLiv) impairs liver regeneration with low survival after partial hepatectomy. Analysis of cell cycle progression suggests a defective exit from quiescence, reduced BrdUrd incorporation, and diminished entry into G2/M phase in PbpΔLiv hepatocytes after partial hepatectomy. PbpΔLiv hepatocytes failed to respond to hepatocyte growth factor/scatter factor, implying that hepatic PBP deficiency affects c-met signaling. Pbp gene disruption also abolishes primary mitogen-induced liver cell proliferative response. Striking abrogation of CCl4-induced hepatocellular proliferation and hepatotoxicity occurred in PbpΔLiv mice pretreated with phenobarbital due to lack of expression of xenobiotic metabolizing enzymes necessary for CCl4 activation. PbpΔLiv mice, chronically exposed to Wy-14,643, a PPARα ligand, revealed a striking proliferative response and clonal expansion of a few Pbpfl/fl hepatocytes that escaped Cre-mediated gene deletion in PbpΔLiv livers, but no proliferative expansion of PBP null hepatocytes was observed. In these PbpΔLiv mice, none of the Wy-14,643-induced hepatic adenomas and hepatocellular carcinomas was derived from PBPΔLiv hepatocytes; all liver tumors developing in PbpΔLiv mice maintained non-recombinant Pbp alleles and retained PBP expression. These studies provide direct evidence in support of a critical role of PBP/TRAP220 in liver regeneration, induction of hepatotoxicity, and hepatocarcinogenesis.

Original languageEnglish (US)
Pages (from-to)17053-17060
Number of pages8
JournalJournal of Biological Chemistry
Volume282
Issue number23
DOIs
StatePublished - Jun 8 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Critical role for transcription coactivator Peroxisome Proliferator- activated Receptor (PPAR)-binding protein/TRAP220 in liver regeneration and PPARα ligand-induced liver tumor development'. Together they form a unique fingerprint.

  • Cite this