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(DeltaLiv)) 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(DeltaLiv) hepatocytes after partial hepatectomy. Pbp(DeltaLiv) 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(DeltaLiv) mice pretreated with phenobarbital due to lack of expression of xenobiotic metabolizing enzymes necessary for CCl(4) activation. Pbp(DeltaLiv) mice, chronically exposed to Wy-14,643, a PPARalpha ligand, revealed a striking proliferative response and clonal expansion of a few Pbp(fl/fl) hepatocytes that escaped Cre-mediated gene deletion in Pbp(DeltaLiv) livers, but no proliferative expansion of PBP null hepatocytes was observed. In these Pbp(DeltaLiv) mice, none of the Wy-14,643-induced hepatic adenomas and hepatocellular carcinomas was derived from PBP(DeltaLiv) hepatocytes; all liver tumors developing in Pbp(DeltaLiv) 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.
Highlights
Transcription cofactors/coregulators consist of corepressors, coactivators, and coactivator- or corepressor-associated proteins, which participate in nuclear receptor-directed transcription [1,2,3]
PBP Is Required for Normal Liver Regeneration—Increased mortality was observed in Pbp⌬Liv mice usually between 2 and 20 h following partial hepatectomy
Oil red O-stained liver sections obtained 24 –72 h after partial hepatectomy showed a moderate degree of macrovesicular steatosis in Pbp⌬Liv mice as compared with minimally visible microvesicular steatosis associated with early stages of normal regenerative response in wild-type mice
Summary
Generation of PBP Conditional Null Mutation in Liver (Pbp⌬Liv), Partial Hepatectomy, and Treatment with CAR and PPAR␣ Agonists—Homozygous mutant mice lacking PBP in hepatocytes (Pbp⌬Liv) were generated as described elsewhere [8]. TCPOBOP was administered intraperitoneally at a single dose of 3 mg/kg body weight. CCl4 (400 mg/kg body weight) was injected intraperitoneally either into phenobarbital-pretreated or untreated mice (100 mg/kg intraperitoneally daily for 3 days (Sigma). BrdUrd (0.5 mg/ml) was administered in drinking water for 3 days and given a single intraperitoneal dose (100 mg/kg body weight) 2 h before killing. Microarray Approach—Total RNA isolated from livers using TRIzol reagent (Invitrogen) was used for preparing biotin-labeled cRNA and purified, fragmented, and hybridized to 430 2.0 arrays (Affymetrix, Santa Clara, CA) as described [17]. Cell doublets were excluded from the analysis performed using Modfit software (Verity Software House, Topsham, ME)
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