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. 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. Transcription cofactors/coregulators consist of corepressors, coactivators, and coactivator- or corepressor-associated proteins, which participate in nuclear receptor-directed transcription (1Lonard D.M. O'Malley B.W. Cell. 2006; 125: 411-414Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar, 2Roeder R.G. FEBS Lett. 2005; 579: 909-915Crossref PubMed Scopus (256) Google Scholar, 3Yu S. Reddy J.K. Biochim. Biophys. Acta. 2007; (in press)Google Scholar). The functional significance for the existence of >200 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 (1Lonard D.M. O'Malley B.W. Cell. 2006; 125: 411-414Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar, 3Yu S. Reddy J.K. Biochim. Biophys. Acta. 2007; (in press)Google Scholar). 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. 3Yu S. Reddy J.K. Biochim. Biophys. Acta. 2007; (in press)Google Scholar for review). For example, the disruption of a coactivator gene such as peroxisome proliferated-activated receptor (PPAR) 2The abbreviations used are: PPAR, peroxisome proliferator-activated receptor; PBP, PPAR-binding protein; TRAP, thyroid hormone receptor-associated protein; PbpΔLiv, PBP liver conditional null; CYP, cytochrome P450; l-PBE, enoyl-CoA hydratase/l-3-hydroxyacyl-CoA dehydrogenase; CAR, constitutive androstane receptor; TCPOBOP, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene; ALT, alanine aminotransferase; IGF, insulin-like growth factor; TGF, transforming growth factor; HGF/SF, hepatocyte growth factor/scatter factor. -binding protein (PBP; also known as TRAP (thyroid hormone receptor-associated protein) 220/DRIP (vitamin D3 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 (4Zhu Y. Qi C. Jain S. Rao M.S. Reddy J.K. J. Biol. Chem. 1997; 272: 25500-25506Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar, 5Yuan C.X. Ito M. Fondell J.D. Fu Z.Y. Roeder R.G. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 7939-7944Crossref PubMed Scopus (390) Google Scholar, 6Rachez C. Lemon B.D. Suldan Z. Bromleigh V. Gamble M. Naar A.M. Erdjument-Bromage H. Tempst P. Freedman L.P. Nature. 1999; 398: 824-828Crossref PubMed Scopus (637) Google Scholar, 7Reddy J.K. Guo D. Jia Y. Yu S. Rao M.S. Taneja R. Advances in Developmental Biology. Vol. 16. Elsevier, San Diego, CA2006: 389-420Google Scholar). To define the in vivo role of this coactivator, we used conditional mutagenesis in mice and found that deletion of the Pbp/Pparbp gene in liver parenchymal cells (PbpΔLiv) results in the abrogation of PPARα ligand-induced pleiotropic effects, indicating that PBP is essential for PPARα signaling (8Jia Y. Qi C. Kashireddi P. Surapureddi S. Zhu Y.J. Rao M.S. Le Roith D. Chambon P. Gonzalez F.J. Reddy J.K. J. Biol. Chem. 2004; 279: 24427-24434Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). Deletion of the Pbp gene in liver also abolished the responses induced by the constitutive androstane receptor (CAR) activators, phenobarbital or 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) and of acetaminophen-induced hepatotoxicity (9Jia Y. Guo G.L. Surapureddi S. Sarkar J. Qi C. Guo D. Xia J. Kashireddi P. Yu S. Cho Y.W. Rao M.S. Kemper B. Ge K. Gonzalez F.J. Reddy J.K. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 12531-12536Crossref PubMed Scopus (50) Google Scholar, 10Guo D. Sarkar J. Ahmed M.R. Viswakarma N. Jia Y. Yu S. Rao M.S. Reddy J.K. Biochem. Biophys. Res. Commun. 2006; 347: 485-495Crossref PubMed Scopus (24) Google Scholar). In this study, we have explored the potential role of PBP in liver regeneration and liver tumor development to test the hypothesis that PBP deficiency in hepatocytes affects the function of many genes that control these complex and vital processes (11Michalopoulos G.K. DeFrances M.C. Science. 1997; 276: 60-66Crossref PubMed Scopus (2905) Google Scholar, 12Fausto N. Campbell J.S. Riehle K.J. Hepatology. 2006; 43: S45-S53Crossref PubMed Scopus (1268) Google Scholar, 13Taub R. Nat. Rev. Mol. Cell Biol. 2004; 5: 836-847Crossref PubMed Scopus (1269) Google Scholar). We have demonstrated a severe impairment of liver regeneration in PbpΔLiv mice subjected to partial hepatectomy. Analysis of immediate early gene expression and cell cycle progression indicates a deficit in exiting from G0 after partial hepatectomy in PBP mutant livers. We have also found that conditional PBP mutant mice do not respond to the cell-proliferating response of mice to TCPOBOP, a well known primary mitogen (14Locker J. Tian J. Carver R. Concas D. Cossu C. Ledda-Columbano G.M. Columbano A. Hepatology. 2003; 38: 314-325Crossref PubMed Scopus (74) Google Scholar, 15Costa R.H. Kalinchenko V.V. Tan Y. Wang J.C. Hepatology. 2005; 42: 1004-1008Crossref PubMed Scopus (31) Google Scholar). Impairment of the cell-proliferative response of PbpΔLiv hepatocytes leads to enhanced proliferative expansion of an occasional PBP+/+ hepatocyte present in these conditional mutant livers, in response to the PPARα ligand Wy-14,643. Accordingly, none of the liver tumors developing in PbpΔLiv mice chronically treated with Wy-14,643 was derived from cells with Pbp null genotype. All liver tumors in these conditional null mutant livers exhibited PBP positivity, implying that PBP is essential for hepatocarcinogenesis. Generation of PBP Conditional Null Mutation in Liver (PbpΔLiv), Partial Hepatectomy, and Treatment with CAR and PPARα Agonists—Homozygous mutant mice lacking PBP in hepatocytes (PbpΔLiv) were generated as described elsewhere (8Jia Y. Qi C. Kashireddi P. Surapureddi S. Zhu Y.J. Rao M.S. Le Roith D. Chambon P. Gonzalez F.J. Reddy J.K. J. Biol. Chem. 2004; 279: 24427-24434Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). Mice were housed in a pathogen-free animal facility under a 12-h light/12-h dark cycle and maintained on standard rodent chow and water ad libitum. Partial hepatectomy was performed under anesthesia to remove 70% of the hepatic mass (16Higgins G.M. Anderson R.M. Arch. Pathol. 1931; 12: 186-202Google Scholar). TCPOBOP was administered intraperitoneally at a single dose of 3 mg/kg body weight. Wy-14,643 (0.125% weight/weight) was in for and 3 For Wy-14,643 was administered in the at a of for To liver CCl4 mg/kg body was intraperitoneally into or mice mg/kg intraperitoneally for 3 days To hepatocyte BrdUrd was administered in water for 3 days and a single dose mg/kg body Mice were by and from the was used for alanine activity an The and all animal Liver were in or for in and with and or for of PBP, or enoyl-CoA hydratase/l-3-hydroxyacyl-CoA the of the (8Jia Y. Qi C. Kashireddi P. Surapureddi S. Zhu Y.J. Rao M.S. Le Roith D. Chambon P. Gonzalez F.J. Reddy J.K. J. Biol. Chem. 2004; 279: 24427-24434Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, Y. Guo G.L. Surapureddi S. Sarkar J. Qi C. Guo D. Xia J. Kashireddi P. Yu S. Cho Y.W. Rao M.S. Kemper B. Ge K. Gonzalez F.J. Reddy J.K. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 12531-12536Crossref PubMed Scopus (50) Google Scholar). The used were and The by hepatocytes was from livers was used for and and to as described S. Viswakarma N. Rao M.S. Reddy J.K. 2004; PubMed Scopus Google Scholar). was and the was by the were and the and from liver was on to and with was performed the and for the c-met M. J. J. 1997; Google Scholar). liver were subjected to to and The protein and were from Cell and were from mouse livers the J. In PubMed Scopus Google Scholar). in response to hepatocyte growth factor/scatter was as described A. K. Proc. Natl. Acad. Sci. U. S. A. 2004; PubMed Scopus Google Scholar). For liver cells were with and was a with a Cell were from the performed PBP for Liver was in PbpΔLiv mice between and partial hepatectomy. The of the regeneration after partial in mice, conditional PBP mutant mice failed to show Liver cell as by BrdUrd incorporation, was in PbpΔLiv mice at all after partial and this after In in Pbpfl/fl BrdUrd was with a in the of hepatocyte with a at and after partial hepatectomy and In these livers, of cell proliferation occurred by after all hepatocyte in Pbpfl/fl livers for PBP In PBP expression in PbpΔLiv mouse livers was in and these in in as with hepatocytes in Pbpfl/fl and In the PbpΔLiv an occasional hepatocyte in the of the liver that escaped Pbp gene disruption exhibited PBP in the These cells with are in as with the PBP null hepatocytes and In these PbpΔLiv mouse livers, BrdUrd was in these hepatocytes which to cells PBP liver after partial hepatectomy a of in PbpΔLiv mice as with with early of response in mice not The hepatic in the PbpΔLiv mouse suggests that into the liver in mice are by the in livers, but this to defective in PbpΔLiv mouse livers J.K. Rao M.S. J. 2006; PubMed Scopus Google Scholar, C. M. C. C. R.G. A. Science. 2006; PubMed Scopus Google Scholar). is well known that PPARα as a in and in the of this nuclear there is hepatic in response to J.K. Rao M.S. J. 2006; PubMed Scopus Google Scholar). is known that PBP is essential for PPARα function (8Jia Y. Qi C. Kashireddi P. Surapureddi S. Zhu Y.J. Rao M.S. Le Roith D. Chambon P. Gonzalez F.J. Reddy J.K. J. Biol. Chem. 2004; 279: 24427-24434Abstract Full Text Full Text PDF PubMed Scopus (99) Google and the of PBP the PPARα after partial hepatectomy. The in PbpΔLiv mouse livers after partial hepatectomy is to the of hepatocytes to and into the in and Partial the in the gene expression in the liver of the control and 3 after partial hepatectomy by the (14Locker J. Tian J. Carver R. Concas D. Cossu C. Ledda-Columbano G.M. Columbano A. Hepatology. 2003; 38: 314-325Crossref PubMed Scopus (74) Google Scholar, S. H. Y. Y. Y. H. J. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). The revealed that genes are or 3 after partial hepatectomy in Pbpfl/fl mice as with PbpΔLiv mice of the genes in the Pbpfl/fl mouse liver in response to partial hepatectomy are immediate early genes known to participate in cell cell growth, and These insulin-like growth protein transcription factor, and growth factor, nuclear and growth and tumor and of signaling 3 R. Nat. Rev. Mol. Cell Biol. 2004; 5: 836-847Crossref PubMed Scopus (1269) Google Scholar, J. Tian J. Carver R. Concas D. Cossu C. Ledda-Columbano G.M. Columbano A. Hepatology. 2003; 38: 314-325Crossref PubMed Scopus (74) Google Scholar, S. H. Y. Y. Y. H. J. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, 2005; Scopus Google Scholar, R. J. 2003; PubMed Scopus Google Scholar, M. H. Biochim. Biophys. Acta. 1997; PubMed Scopus Google Scholar). the of expression of and in Pbpfl/fl livers 3 For example, which is known to a in liver regeneration after partial hepatectomy M. H. Biochim. Biophys. Acta. 1997; PubMed Scopus Google of expression in PBP+/+ mice but not in PbpΔLiv mice we not the of induction of these genes the of liver regeneration, with we of expression of this gene to in Pbpfl/fl livers are of liver regeneration R. J. 2003; PubMed Scopus Google and these immediate early genes are involved in the of liver cells after partial hepatectomy for and (11Michalopoulos G.K. DeFrances M.C. Science. 1997; 276: 60-66Crossref PubMed Scopus (2905) Google Scholar, 12Fausto N. Campbell J.S. Riehle K.J. Hepatology. 2006; 43: S45-S53Crossref PubMed Scopus (1268) Google Scholar, 13Taub R. Nat. Rev. Mol. Cell Biol. 2004; 5: 836-847Crossref PubMed Scopus (1269) Google Scholar). of these cell cycle and cell growth factors in PbpΔLiv mouse liver the of hepatocellular proliferative response partial hepatectomy. In PbpΔLiv mouse genes were or 3 partial hepatectomy as with mice These transforming growth receptor and known to cell cell cycle by the expression of K. R. K. 2005; PubMed Scopus Google Scholar). a of cell a role in response at after partial hepatectomy (11Michalopoulos G.K. DeFrances M.C. Science. 1997; 276: 60-66Crossref PubMed Scopus (2905) Google Scholar, 12Fausto N. Campbell J.S. Riehle K.J. Hepatology. 2006; 43: S45-S53Crossref PubMed Scopus (1268) Google Scholar). We found that receptor is at in PbpΔLiv mouse liver as early as 3 after partial implying that the signaling with liver regeneration in PbpΔLiv mice and partial in PBP+/+ liver cell and cell growth protein Transcription in liver cell and cell growth of transcription 3 in a To the for defective liver regeneration, we the expression of involved in cell cycle of with exit from and of between and after partial hepatectomy in Pbpfl/fl mice, but these were diminished and in in PbpΔLiv mice is to entry into by S. H. Y. Y. Y. H. J. 2004; Full Text Full Text PDF PubMed Scopus Google we the in the of and In the Pbpfl/fl mouse the of and were in the PbpΔLiv The expression of and is under the control of immediate early such as and expression exit from the G0 phase Res. Google Scholar). and and phase of the cell cycle Res. Google Scholar). In Pbpfl/fl livers, the of these and such were not readily in PbpΔLiv mouse liver after partial hepatectomy The after partial hepatectomy in Pbpfl/fl mouse and this was not in the PbpΔLiv mouse revealed liver cells in phase and in G2/M in PbpΔLiv mouse livers after partial hepatectomy. was in to and G2/M in the control not These with in immediate early gene expression and in BrdUrd incorporation, that disruption of Pbp gene in liver results in reduced and a in entry to the G2/M phase of the cell We also that primary hepatocytes from PbpΔLiv mice failed to in response to in a standard receptor a and defective c-met signaling in liver regeneration and in the and progression of M. J. J. 1997; Google Scholar, A. K. Proc. Natl. Acad. Sci. U. S. A. 2004; PubMed Scopus Google Scholar, S. D. J. 2006; PubMed Scopus Google Scholar, M. M. C. C. Proc. Natl. Acad. Sci. U. S. A. 2004; PubMed Scopus Google Scholar). revealed a in c-met in PbpΔLiv a in signaling The signaling is for liver regeneration, and that PBP deletion affects this signaling in PbpΔLiv in to a TCPOBOP, a ligand and for the nuclear receptor CAR, hepatocellular proliferation (14Locker J. Tian J. Carver R. Concas D. Cossu C. Ledda-Columbano G.M. Columbano A. Hepatology. 2003; 38: 314-325Crossref PubMed Scopus (74) Google Scholar, 15Costa R.H. Kalinchenko V.V. Tan Y. Wang J.C. Hepatology. 2005; 42: 1004-1008Crossref PubMed Scopus (31) Google Scholar). We a of hepatocellular proliferation in Pbpfl/fl and PbpΔLiv mice and after a single of in liver to body as well as BrdUrd were in Pbpfl/fl mice at after TCPOBOP but PbpΔLiv mice no such and We also the of TCPOBOP on the of expression of CAR genes in liver between and after Deletion of Pbp gene induction of genes after TCPOBOP TCPOBOP in the induction of hepatic and that occurred in Pbpfl/fl mice Y. S. N. H. M. M. J. 2005; PubMed Scopus Google Scholar, J. J. M. S. Science. Scopus Google Scholar, P. M. Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar). in protein and CAR was in PbpΔLiv mice To the deficit in liver proliferation after TCPOBOP we the cell In Pbpfl/fl mice, and to in liver at and after TCPOBOP but not in PbpΔLiv which cell growth, a of expression at and after TCPOBOP in Pbpfl/fl mice in PbpΔLiv In the livers of PBP+/+ mice, the of was PbpΔLiv mice These that the of PBP in hepatocytes affects the function of CAR and that CAR ligand TCPOBOP not hepatocellular proliferative response and to xenobiotic metabolizing Mice to CCl4-induced the of hepatic regeneration and in PbpΔLiv mice, we used a single of CCl4 to hepatic to the response. CCl4 is by and by to a and Y. S. N. H. M. M. J. 2005; PubMed Scopus Google Scholar). In Pbpfl/fl mice not pretreated with CCl4 induced liver cell proliferation and a of hepatic in the at days with in with phenobarbital in of CCl4-induced in Pbpfl/fl livers with of proliferation in these Pbpfl/fl mice was at after CCl4 and this for days of CCl4-induced liver was at days in these mice and In in hepatocellular proliferation were not in PbpΔLiv mice CCl4 or with phenobarbital and of is that CCl4 failed to hepatocellular in PbpΔLiv mice with phenobarbital These results in the of PBP, phenobarbital to CCl4 in the abrogation of We reported that PBP is involved in the of hepatic CAR function and the induction of enzymes and that PBP deficiency in liver hepatotoxicity (9Jia Y. Guo G.L. Surapureddi S. Sarkar J. Qi C. Guo D. Xia J. Kashireddi P. Yu S. Cho Y.W. Rao M.S. Kemper B. Ge K. Gonzalez F.J. Reddy J.K. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 12531-12536Crossref PubMed Scopus (50) Google Scholar, 10Guo D. Sarkar J. Ahmed M.R. Viswakarma N. Jia Y. Yu S. Rao M.S. Reddy J.K. Biochem. Biophys. Res. Commun. 2006; 347: 485-495Crossref PubMed Scopus (24) Google Scholar). we reported that the of PBP in liver cells of the xenobiotic receptor CAR into the hepatocyte under in vivo and in in the of CAR (9Jia Y. Guo G.L. Surapureddi S. Sarkar J. Qi C. Guo D. Xia J. Kashireddi P. Yu S. Cho Y.W. Rao M.S. Kemper B. Ge K. Gonzalez F.J. Reddy J.K. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 12531-12536Crossref PubMed Scopus (50) Google Scholar, 10Guo D. Sarkar J. Ahmed M.R. Viswakarma N. Jia Y. Yu S. Rao M.S. Reddy J.K. Biochem. Biophys. Res. Commun. 2006; 347: 485-495Crossref PubMed Scopus (24) Google Scholar). CAR gene transcription the of CAR in the hepatocyte and coactivator PBP, by of role as an for is for the and of CAR in the to gene transcription D. Sarkar J. Ahmed M.R. Viswakarma N. Jia Y. Yu S. Rao M.S. Reddy J.K. Biochem. Biophys. Res. Commun. 2006; 347: 485-495Crossref PubMed Scopus (24) Google Scholar). of CAR activity by the transcription coactivator PBP an for or liver and of nuclear receptor coactivator PBP function as to liver PBP for Wy-14,643-induced and a peroxisome and a rodent liver by the nuclear receptor PPARα M.S. Reddy J.K. PubMed Scopus Google Scholar, J.K. J. Pathol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, Gonzalez F.J. 1997; PubMed Scopus Google Scholar). In of the of PbpΔLiv hepatocytes to liver regeneration induced by partial hepatectomy and TCPOBOP we PBP is for Wy-14,643-induced hepatocyte proliferation and hepatic of Wy-14,643 to PbpΔLiv mice in the proliferation of liver cells with and these cells were for BrdUrd as well as PBP and that these cell which to and in response to Wy-14,643, are the hepatocytes that escaped PBP gene deletion is that these cells a in to in a the of hepatocytes do not PBP and are to the These results that few hepatocytes present in PbpΔLiv mouse growth the hepatocyte to show cell proliferation and induction of enzymes J.K. J. Pathol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). for l-PBE, the of the J.K. J. Pathol. 2004; Full Text Full Text PDF PubMed Scopus Google that induction in hepatocytes and not in liver These show that PBP is for Wy-14,643-induced proliferative expansion of hepatocytes and for the induction of the we the by hepatocytes and of PbpΔLiv mouse liver at and 3 of with Wy-14,643 by The hepatocytes in the PbpΔLiv mouse but at the to In of this response in PbpΔLiv mouse livers, we to PBP is for mouse liver tumor development in response to Wy-14,643, a J.K. J. Pathol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). of Wy-14,643 PbpΔLiv mice and Pbpfl/fl were and livers were for the of The livers of PbpΔLiv and Pbpfl/fl mice revealed tumors that were all liver The liver tumor was in in Pbpfl/fl in PbpΔLiv We tumors from and PbpΔLiv for the expression of PBP to of the tumors developing in PbpΔLiv mice were derived from hepatocytes a and all adenomas and hepatocellular carcinomas that in PbpΔLiv mice were The of liver in PbpΔLiv mice not PBP of the tumors developing in PbpΔLiv mice were implying that PbpΔLiv hepatocytes are to All tumors in the Pbpfl/fl mouse liver for PBP, and in these livers, hepatocytes in all also PBP these we that with Wy-14,643 and proliferation of Pbpfl/fl hepatocytes in PbpΔLiv mice, and all of these hepatocytes respond to the of this PPARα ligand on there is an of These the potential to In in hepatocytes were not in PbpΔLiv mouse livers due to the days after partial days with that a few cells in the PbpΔLiv mouse liver are the importance of the of cell proliferation of these Pbpfl/fl cells to the is that hepatocytes in PbpΔLiv mouse liver are for of the hepatocyte these cells to for liver tumor development in a the is to PPARα ligand-induced hepatocellular proliferation and the induction of generated by enzymes as a of PBP deficiency M.S. Reddy J.K. PubMed Scopus Google Scholar, J.K. J. Pathol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, Gonzalez F.J. 1997; PubMed Scopus Google Scholar). is known that mice Wy-14,643 in the for to of mice this liver a critical role by PPARα in peroxisome M.S. Reddy J.K. PubMed Scopus Google Scholar, Gonzalez F.J. 1997; PubMed Scopus Google Scholar). is to that PbpΔLiv mice mice with to the induced by PPARα J.K. J. Pathol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). these that PBP is essential for Wy-14,643-induced hepatocyte proliferation and to the PBP null hepatocytes function as for such as V.V. Wang V. J. B. A. P. R.H. 2004; PubMed Scopus Google Scholar). Transcription coactivator as an for and disruption of this gene in the mouse results in embryonic lethality. gene that PBP is essential for the function of nuclear PPARα and CAR in critical role for PBP in the induced transcriptional of nuclear in liver is by in and gene transcription (8Jia Y. Qi C. Kashireddi P. Surapureddi S. Zhu Y.J. Rao M.S. Le Roith D. Chambon P. Gonzalez F.J. Reddy J.K. J. Biol. Chem. 2004; 279: 24427-24434Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, Y. Guo G.L. Surapureddi S. Sarkar J. Qi C. Guo D. Xia J. Kashireddi P. Yu S. Cho Y.W. Rao M.S. Kemper B. Ge K. Gonzalez F.J. Reddy J.K. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 12531-12536Crossref PubMed Scopus (50) Google Scholar). of PbpΔLiv mice to PPARα and CAR are to mice lacking the receptor J. J. M. S. Science. Scopus Google Scholar, Gonzalez F.J. 1997; PubMed Scopus Google Scholar). The results described provide evidence for the essential role of PBP in liver regeneration induced by partial hepatectomy. Mice lacking PBP in liver cells exhibited no and failed to exit the phase of the cell regeneration was also not in these PBP null livers exposed to CAR ligand is PbpΔLiv mice liver tumors chronically treated with PPARα ligand Wy-14,643 M.S. Reddy J.K. PubMed Scopus Google Scholar, J.K. J. Pathol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, Gonzalez F.J. 1997; PubMed Scopus Google none of the tumors from PBP null All liver tumors PBP, and growth and was in to the in these PbpΔLiv livers. These for the the of a transcription coactivator in hepatocellular response and in hepatocarcinogenesis. These Pbpfl/fl mice provide an to the role of this coactivator in gene expression in a
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