Critical Role for Transcription Coactivator Peroxisome Proliferator-activated Receptor (PPAR)-binding Protein/TRAP220 in Liver Regeneration and PPARα Ligand-induced Liver Tumor Development

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 (Pbp ⌬Liv ) 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 G 2 /M phase in Pbp ⌬Liv hepatocytes after partial hepatectomy. Pbp ⌬Liv 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 CCl 4 -induced hepatocellular proliferation and hepatotoxicity occurred in Pbp ⌬Liv mice pretreated with phenobarbital due to lack of expression of xenobiotic metabolizing enzymes necessary for CCl 4 activation. Pbp ⌬Liv mice, chronically exposed to Wy-14,643, a PPAR␣ ligand, revealed a striking proliferative response and clonal expansion of a few Pbp fl/fl hepatocytes that escaped Cre-mediated gene deletion in Pbp ⌬Liv livers, but no proliferative expansion of PBP null hepatocytes was observed. In these Pbp ⌬Liv mice, none of the Wy-14,643-induced hepatic adenomas and hepatocellular carcinomas was derived from PBP ⌬Liv hepatocytes; all liver tumors developing in Pbp ⌬Liv 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.Transcription cofactors/coregulators consist of corepressors, coactivators, and coactivator-or corepressor-associated proteins, which participate in nuclear receptor-directed transcription (1-3). The functional significance for the existence of Ͼ200 nuclear receptor cofactors is not readily evident, but there is an increasing recognition of the general importance of some of these molecules in gene expression, embryogenesis, cell growth, and oncogenesis, as well as energy and xenobiotic metabolism (1, 3). Emerging gene knock-out mouse models show that some of the coactivators that directly bind to transcription factors to enhance gene expression are essential for embryonic growth and survival (see Ref. 3 for review). For example, the disruption of a coactivator gene such as peroxisome proliferated-activated receptor (PPAR) 2 -binding protein (PBP; also known as TRAP (thyroid hormone receptor-associated protein) 220/DRIP (vitamin D 3 receptor-interacting protein) 205)/Med1 (Mediator 1)) is embryonically lethal between gestational days 11.5 and 12.5, implying that this coactivator is widely involved in the transcriptional activity of many transcription factors (4, 5-7). To define the in vivo role of this coactivator, we used conditional mutagenesis in mice and found that deletion of the Pbp/Pparbp gen...

Comprehensive and quantitative proteome profiling of the mouse liver and plasma

“…23 Proteins associated with signaling pathways of relevance to liver biology (platelet-derived growth factor, interleukin-4, epidermal growth factor, and insulin receptor signaling pathways) were also identified among the proteins common to liver tissue and plasma. They included peroxisome proliferator-activated receptor binding protein, an important player in liver regeneration, 24 epidermal growth factor receptor, involved in the proliferation and mitogenesis of hepatocytes, 25 inositol 1,4,5-triphosphate receptor, which has been found to be decreased in bile ducts of patients with primary biliary cirrhosis, 26 and signal transducer and activator of transcription 2, which promotes antiviral defense in the liver. 27 Finally, 10 members of the A disintegrin and metalloproteinase protein and A disintegrin-like and metalloproteinase with thrombospondin motifs families were identified.…”

Transcriptional Regulation of Hepatic Fatty Acid Metabolism

“…Following the binding of an exogenously added activator to its LBD, the mobility of PPARa in the nucleus is reduced, mainly due to the recruitment of a larger complex of coactivators (Feige et al, 2005;Tudor et al, 2007). Such a complex has indeed been isolated from rat liver (Surapureddi et al, 2002) and several coactivators associated with PPARa-RXR have been identified such as CBP/ p300 (Dowell et al, 1997;Tudor et al, 2007), PGC-1a (Vega et al, 2000), members of the SWI/SNF chromatin remodelling complexes (Surapureddi et al, 2002) and of Mediator complexes (Jia et al, 2004;Matsumoto et al, 2007). These coregulators mediate the effects of PPARa-RXR at the transcription level through their action on the chromatin and their interactions with the basal transcription machinery (Fig.…”

Transcriptional co-factors and hepatic energy metabolism

“…anymore [135]. Additionally, the liver specific ablation of TRAP220 attenuated hepatic steatosis induced by the glucocorticoid receptor (GR) agonist dexamethasone [136].…”