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

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 (Pbp^ΔLiv) 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 Pbp^ΔLiv hepatocytes after partial hepatectomy. Pbp^ΔLiv 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 Pbp^ΔLiv mice pretreated with phenobarbital due to lack of expression of xenobiotic metabolizing enzymes necessary for CCl₄ activation. Pbp^ΔLiv mice, chronically exposed to Wy-14,643, a PPARα ligand, revealed a striking proliferative response and clonal expansion of a few Pbp^fl/fl hepatocytes that escaped Cre-mediated gene deletion in Pbp^ΔLiv livers, but no proliferative expansion of PBP null hepatocytes was observed. In these Pbp^ΔLiv mice, none of the Wy-14,643-induced hepatic adenomas and hepatocellular carcinomas was derived from PBP^ΔLiv hepatocytes; all liver tumors developing in Pbp^ΔLiv 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.