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Satdarshan P.s. Monga - One of the best experts on this subject based on the ideXlab platform.
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Yap is crucial for CAR‐driven Hepatocyte Proliferation, but not for induction of drug metabolism genes in mice
Hepatology (Baltimore Md.), 2020Co-Authors: Bharat Bhushan, Satdarshan P.s. Monga, Shirish Paranjpe, Wendy M Mars, Laura Molina, Kelly Koral, John Stoops, Swati Banerjee, Anne Orr, Joseph LockerAbstract:Constitutive androstane receptor (CAR) agonists, such as TCPOBOP, are known to cause robust Hepatocyte Proliferation and hepatomegaly in mice along with induction of drug metabolism genes, without any associated liver injury. Yes-associated protein (Yap) is a key transcription regulator that tightly controls organ size including that of liver. Ours and other previous studies suggested increased nuclear localization and activation of Yap after TCPOBOP-treatment in mice and potential role of Yap in CAR-driven proliferative response. Here, we investigated a direct role of Yap in CAR-driven hepatomegaly and Hepatocyte Proliferation using Hepatocyte-specific Yap-KO mice. AAV8-TBG-CRE vector was injected to Yap-floxed mice for achieving Hepatocyte-specific Yap deletion followed by TCPOBOP-treatment. Yap deletion did not decrease protein expression of CAR or CAR-driven induction of drug metabolism genes (including Cyp2b10, Cyp2c55 and Ugt1a1). However, Yap deletion substantially reduced TCPOBOP-induced Hepatocyte Proliferation. TCPOBOP-driven cell cycle activation was disrupted in Yap-KO mice due to delayed (and decreased) induction of cyclin D1 and higher expression of p21, resulting in decreased phosphorylation of retinoblastoma (Rb) protein. Further, induction of other cyclins, which are sequentially involved in progression through cell cycle (including cyclin E1, A2 and B1) and important mitotic regulators (such as aurora B kinase and polo-like kinase 1) was remarkably reduced in Yap-KO mice. Microarray analysis revealed that 26% of TCPOBOP-responsive genes mainly related to Proliferation, but not to drug metabolism, were altered by Yap deletion. Yap regulated these Proliferation genes via alerting expression of Myc and Foxm1, two critical transcriptional regulators of CAR-mediated Hepatocyte Proliferation. Conclusion: Our study revealed an important role of Yap signaling in CAR-driven Hepatocyte Proliferation; however, CAR-driven induction of drug metabolism genes was independent of Yap.
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yap is crucial for car driven Hepatocyte Proliferation but not for induction of drug metabolism genes in mice
Hepatology, 2020Co-Authors: Bharat Bhushan, Satdarshan P.s. Monga, Shirish Paranjpe, Wendy M Mars, Laura Molina, Kelly Koral, John Stoops, Swati Banerjee, Anne Orr, Joseph LockerAbstract:Constitutive androstane receptor (CAR) agonists, such as TCPOBOP, are known to cause robust Hepatocyte Proliferation and hepatomegaly in mice along with induction of drug metabolism genes, without any associated liver injury. Yes-associated protein (Yap) is a key transcription regulator that tightly controls organ size including that of liver. Ours and other previous studies suggested increased nuclear localization and activation of Yap after TCPOBOP-treatment in mice and potential role of Yap in CAR-driven proliferative response. Here, we investigated a direct role of Yap in CAR-driven hepatomegaly and Hepatocyte Proliferation using Hepatocyte-specific Yap-KO mice. AAV8-TBG-CRE vector was injected to Yap-floxed mice for achieving Hepatocyte-specific Yap deletion followed by TCPOBOP-treatment. Yap deletion did not decrease protein expression of CAR or CAR-driven induction of drug metabolism genes (including Cyp2b10, Cyp2c55 and Ugt1a1). However, Yap deletion substantially reduced TCPOBOP-induced Hepatocyte Proliferation. TCPOBOP-driven cell cycle activation was disrupted in Yap-KO mice due to delayed (and decreased) induction of cyclin D1 and higher expression of p21, resulting in decreased phosphorylation of retinoblastoma (Rb) protein. Further, induction of other cyclins, which are sequentially involved in progression through cell cycle (including cyclin E1, A2 and B1) and important mitotic regulators (such as aurora B kinase and polo-like kinase 1) was remarkably reduced in Yap-KO mice. Microarray analysis revealed that 26% of TCPOBOP-responsive genes mainly related to Proliferation, but not to drug metabolism, were altered by Yap deletion. Yap regulated these Proliferation genes via alerting expression of Myc and Foxm1, two critical transcriptional regulators of CAR-mediated Hepatocyte Proliferation. Conclusion: Our study revealed an important role of Yap signaling in CAR-driven Hepatocyte Proliferation; however, CAR-driven induction of drug metabolism genes was independent of Yap.
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Bromodomain and Extraterminal (BET) Proteins Regulate Hepatocyte Proliferation in Hepatocyte-Driven Liver Regeneration.
The American journal of pathology, 2018Co-Authors: Jacquelyn O. Russell, Harvinder Saggi, Sucha Singh, Minakshi Poddar, Donghun Shin, Satdarshan P.s. MongaAbstract:Bromodomain and extraterminal (BET) proteins recruit key components of basic transcriptional machinery to promote gene expression. Aberrant expression and mutations in BET genes have been identified in many malignancies. Small molecule inhibitors of BET proteins such as JQ1 have shown efficacy in preclinical cancer models, including affecting growth of hepatocellular carcinoma. BET proteins also regulate cell Proliferation in nontumor settings. We recently showed that BET proteins regulate cholangiocyte-driven liver regeneration. Here, we studied the role of BET proteins in Hepatocyte-driven liver regeneration in partial hepatectomy (PHx) and acetaminophen-induced liver injury models in mice and zebrafish. JQ1 was injected 2 or 16 hours after PHx in mice to determine effect on hepatic injury, regeneration, and signaling. Mice treated with JQ1 after PHx displayed increased liver injury and a near-complete inhibition of Hepatocyte Proliferation. Levels of Ccnd1 mRNA and Cyclin D1 protein were reduced in animals injected with JQ1 16 hours after PHx and were even further reduced in animals injected with JQ1 2 hours after PHx. JQ1-treated zebrafish larvae after acetaminophen-induced injury also displayed notably impaired Hepatocyte Proliferation. In both models, Wnt signaling was prominently suppressed by JQ1. Our results show that BET proteins regulate Hepatocyte Proliferation-driven liver regeneration, and Wnt signaling is particularly sensitive to BET protein inhibition.
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Thyroid Hormone Receptor β Agonist Induces β-Catenin-Dependent Hepatocyte Proliferation in Mice: Implications in Hepatic Regeneration.
Gene expression, 2016Co-Authors: Tamara Feliciano Alvarado, Sucha Singh, Minakshi Poddar, Morgan Preziosi, Kari Nejak-bowen, Elisabetta Puliga, Amedeo Columbano, Satdarshan P.s. MongaAbstract:Triiodothyronine (T3) induces Hepatocyte Proliferation in rodents. Recent work has shown molecular mechanism for T3's mitogenic effect to be through activation of β-catenin signaling. Since systemic side effects of T3 may preclude its clinical use, and Hepatocytes mostly express T3 hormone receptor β (TRβ), we investigated if selective TRβ agonists like GC-1 may also have β-catenin-dependent Hepatocyte mitogenic effects. Here we studied the effect of GC-1 and T3 in conditional knockouts of various Wnt pathway components. We also assessed any regenerative advantage of T3 or GC-1 when given prior to partial hepatectomy in mice. Mice administered GC-1 showed increased pSer675-β-catenin, cyclin D1, BrdU incorporation, and PCNA. No abnormalities in liver function tests were noted. GC-1-injected liver-specific β-catenin knockouts (β-catenin LKO) showed decreased Proliferation when compared to wild-type littermates. To address if Wnt signaling was required for T3- or GC-1-mediated Hepatocyte Proliferation, we used LRP5-6-LKO, which lacks the two redundant Wnt coreceptors. Surprisingly, decreased Hepatocyte Proliferation was also evident in LRP5-6-LKO in response to T3 and GC-1, despite increased pSer675-β-catenin. Further, increased levels of active β-catenin (hypophosphorylated at Ser33, Ser37, and Thr41) were evident after T3 and GC-1 treatment. Finally, mice pretreated with T3 or GC-1 for 7 days followed by partial hepatectomy showed a significant increase in Hepatocyte Proliferation both at the time (T0) and 24 h after surgery. In conclusion, like T3, TRβ-selective agonists induce Hepatocyte Proliferation through β-catenin activation via both PKA- and Wnt-dependent mechanisms and confer a regenerative advantage following surgical resection. Hence, these agents may be useful regenerative therapies in liver transplantation or other surgical settings.
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WNT5A inhibits Hepatocyte Proliferation and concludes β-catenin signaling in liver regeneration.
The American journal of pathology, 2015Co-Authors: Jing Yang, Antonella Cusimano, Jappmann K. Monga, Morgan Preziosi, Filippo Pullara, Guillermo Calero, Richard A. Lang, Terry P Yamaguchi, Kari Nejak-bowen, Satdarshan P.s. MongaAbstract:Activation of Wnt/β-catenin signaling during liver regeneration (LR) after partial hepatectomy (PH) is observed in several species. However, how this pathway is turned off when Hepatocyte Proliferation is no longer required is unknown. We assessed LR in liver-specific knockouts of Wntless ( Wls -LKO), a protein required for Wnt secretion from a cell. When subjected to PH, Wls -LKO showed prolongation of Hepatocyte Proliferation for up to 4 days compared with littermate controls. This coincided with increased β-catenin–T-cell factor 4 interaction and cyclin-D1 expression. Wls -LKO showed decreased expression and secretion of inhibitory Wnt5a during LR. Wnt5a expression increased between 24 and 48 hours, and Frizzled-2 between 24 and 72 hours, after PH in normal mice. Treatment of primary mouse Hepatocytes and liver tumor cells with Wnt5a led to a notable decrease in β-catenin–T-cell factor activity, cyclin-D1 expression, and cell Proliferation. Intriguingly, Wnt5a-LKO did not display any prolongation of LR because of compensation by other cells. In addition, Wnt5a-LKO Hepatocytes failed to respond to exogenous Wnt5a treatment in culture because of a compensatory decrease in Frizzled-2 expression. In conclusion, we demonstrate Wnt5a to be, by default, a negative regulator of β-catenin signaling and Hepatocyte Proliferation, both in vitro and in vivo . We also provide evidence that the Wnt5a/Frizzled-2 axis suppresses β-catenin signaling in Hepatocytes in an autocrine manner, thereby contributing to timely conclusion of the LR process.
Kouichi Yoshinari - One of the best experts on this subject based on the ideXlab platform.
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Role of Nuclear Receptors PXR and CAR in Xenobiotic-Induced Hepatocyte Proliferation and Chemical Carcinogenesis
Biological & pharmaceutical bulletin, 2019Co-Authors: Kouichi YoshinariAbstract:Nuclear receptors pregnane X receptor (PXR) and constitutive active/androstane receptor (CAR) are xenobiotic-responsible transcriptional factors that belong to the same subfamily and are expressed abundantly in the liver. They play crucial roles in various liver functions including xenobiotic disposition and energy metabolism. CAR is also involved in xenobiotic-induced Hepatocyte Proliferation and hepatocarcinogenesis in rodents. However, there are some open questions on the association between chemical carcinogenesis and these nuclear receptors. These include the molecular mechanism for CAR-mediated Hepatocyte Proliferation and hepatocarcinogenesis. Another important question is whether PXR is associated with Hepatocyte Proliferation. We have recently reported a novel and unique function of PXR associated with murine Hepatocyte Proliferation: PXR activation alone does not induce Hepatocyte Proliferation but accelerates Hepatocyte Proliferation induced by various types of stimuli including CAR- or peroxisome proliferator-activated receptor alpha activating compounds, liver injury, and growth factors. We have also reported a role of yes-associated protein (YAP), a transcriptional cofactor controlling organ size and cell growth under the Hippo pathway, in CAR-mediated Hepatocyte Proliferation in mice. In this review, I will introduce our recent results as well as related studies on the roles of PXR and CAR in xenobiotic-induced Hepatocyte Proliferation and their molecular mechanisms.
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Acceleration of murine Hepatocyte Proliferation by imazalil through the activation of nuclear receptor PXR.
The Journal of toxicological sciences, 2018Co-Authors: Shohei Yoshimaru, Ryota Shizu, Satoshi Tsuruta, Yuto Amaike, Makoto Kano, Takuomi Hosaka, Takamitsu Sasaki, Kouichi YoshinariAbstract:The nuclear receptor pregnane X receptor (PXR) plays a major role in the xenobiotic-induced expression of drug-metabolizing enzymes. PXR activation is also associated with several adverse events in the liver. Especially, the receptor enhances Hepatocyte Proliferation mediated by chemical liver tumor promoters, suggesting that exposure to PXR activators increases the risk of liver cancer. In this study, we have investigated the influences of food additives on PXR to understand their potential adverse effects when they are taken in combination with other chemical compounds. We first screened 25 food additives and related compounds for their PXR-activating ability using reporter assays in HepG2 cells expressing mouse PXR, and found that imazalil dose-dependently activated mouse PXR. Next, to investigate whether imazalil could activate mouse PXR in vivo, mice were treated with imazalil and we found that imazalil treatment increased hepatic mRNA levels of Cyp3a11, a PXR target gene. Finally, to investigate the influence of imazalil exposure on the Hepatocyte Proliferation induced by nuclear receptor constitutive active/androstane receptor (CAR), mice were treated with imazalil with or without mouse CAR activator TCPOBOP. Although imazalil alone did not induce Hepatocyte Proliferation, co-treatment with imazalil facilitated the TCPOBOP-dependent Proliferation, indicated by the increases in cell Proliferation marker levels, Ki-67-positive nuclei and Mcm2 mRNA levels. These results suggest that in mice imazalil activates PXR to enhance Hepatocyte Proliferation mediated by CAR-activating liver tumor promoters.
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PXR stimulates growth factor-mediated Hepatocyte Proliferation by cross-talk with the FOXO transcription factor
The Biochemical journal, 2015Co-Authors: Ryota Shizu, Taiki Abe, Satoshi Benoki, Miki Takahashi, Susumu Kodama, Masaaki Miayata, Atsushi Matsuzawa, Kouichi YoshinariAbstract:Growth factor-mediated Hepatocyte Proliferation is crucial in liver regeneration and the recovery of liver function after injury. The nuclear receptor, pregnane X receptor (PXR), is a key transcription factor for the xenobiotic-induced expression of genes associated with various liver functions. Recently, we reported that PXR activation stimulates xenobiotic-induced Hepatocyte Proliferation. In the present study, we investigated whether PXR activation also stimulates growth factor-mediated Hepatocyte Proliferation. In G0 phase-synchronized, immortalized mouse Hepatocytes, serum or epidermal growth factor treatment increased cell growth and this growth was augmented by the expression of mouse PXR and co-treatment with pregnenolone 16α-carbonitrile (PCN), a PXR ligand. In a liver regeneration model using carbon tetrachloride, PCN treatment enhanced the injury-induced increase in the number of Ki-67-positive nuclei as well as Ccna2 and Ccnb1 mRNA levels in wild-type (WT) but not Pxr-null mice. Chronological analysis of this model demonstrated that PCN treatment shifted the maximum cell Proliferation to an earlier time point and increased the number of M-phase cells at those time points. In WT but not Pxr-null mice, PCN treatment reduced hepatic mRNA levels of genes involved in the suppression of G0/G1- and G1/S-phase transition, e.g. Rbl2, Cdkn1a and Cdkn1b. Analysis of the Rbl2 promoter revealed that PXR activation inhibited its Forkhead box O3 (FOXO3)-mediated transcription. Finally, the PXR-mediated enhancement of Hepatocyte Proliferation was inhibited by the expression of dominant active FOXO3 in vitro. The results of the present study suggest that PXR activation stimulates growth factor-mediated Hepatocyte Proliferation in mice, at least in part, through inhibiting FOXO3 from accelerating cell-cycle progression.
Lisa M. Colletti - One of the best experts on this subject based on the ideXlab platform.
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stem cell factor and its receptor c kit are important for Hepatocyte Proliferation in wild type and tumor necrosis factor receptor 1 knockout mice after 70 hepatectomy
Surgery, 2008Co-Authors: Xiaodan Ren, Lisa M. CollettiAbstract:Background Stem cell factor (SCF) has well-known proliferative effects on hematopoietic cells. SCF also has effects on differentiation and Proliferation in other cell types. Interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α have proliferative effects in the liver. Recent studies in our laboratory have linked SCF's hepatoproliferative actions to those of IL-6, demonstrating that IL-6–induced Hepatocyte Proliferation depends, at least in part, on SCF. We now hypothesize that TNF-α's hepatoproliferative effects are also dependent on SCF. Methods and Results In vitro studies using primary mouse Hepatocytes show that SCF is induced by TNF-α; anti-SCF antibody treatment in this system inhibits TNF-α–induced Hepatocyte Proliferation, suggesting that TNF-α–induced Hepatocyte Proliferation is also SCF dependent. Additional in vivo experiments were performed in which wild type and/or TNF-α receptor-1 knockout mice (TNFR1−/−) were subjected to 70% hepatectomy or sham laparotomy. TNFR1−/− mice are known to have delayed hepatic regeneration after partial hepatectomy. Initial experiments demonstrated that the SCF receptor, c-kit, is upregulated after partial hepatectomy in wild-type mice, further emphasizing the importance of this system in the restoration of hepatic mass. SCF administration to TNFR1−/− mice in the context of partial hepatectomy restores Hepatocyte Proliferation to normal. Further, SCF administration to TNFR1−/− mice before hepatectomy increases phosphotyrosine signal transducer and activator (p-stat-3) levels, suggesting that SCF-induced increases in Hepatocyte Proliferation may also be stat-3 mediated. Conclusions These data suggest that TNF-α–induced Hepatocyte Proliferation depends, at least in part, on SCF and that SCF and its receptor, c-kit, are important for the liver's regenerative processes.
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Stem cell factor restores Hepatocyte Proliferation in IL-6 knockout mice following 70% hepatectomy
The Journal of clinical investigation, 2003Co-Authors: Xiaodan Ren, Cory M. Hogaboam, Audra Carpenter, Lisa M. CollettiAbstract:Stem cell factor (SCF) is a molecule with known proliferative effects on hematopoietic cells. More recent studies suggest that this molecule may also have effects on cellular differentiation and Proliferation in other types of cells. The current investigations demonstrate that there is a large reservoir of SCF in the liver, that hepatic SCF levels change dramatically following partial hepatectomy in mice, and that SCF blockade, either by administration of anti-SCF antibodies or by using genetically altered, SCF-deficient mice, inhibits Hepatocyte Proliferation after partial hepatectomy; if SCF is replaced in the genetically SCF-deficient mice after partial hepatectomy, Hepatocyte Proliferation is restored to that seen in WT animals. Furthermore, SCF administration to IL-6 knockout mice also restores Hepatocyte Proliferation to normal. In vitro studies using primary mouse Hepatocytes demonstrate that SCF causes Hepatocyte Proliferation and is induced by IL-6 and that treatment with anti-SCF antibodies inhibits IL-6-induced Hepatocyte Proliferation. Further in vivo studies in IL-6 knockout mice demonstrate that SCF administration to these animals increases p-stat3 levels, suggesting that the SCF-induced increase in Hepatocyte Proliferation in this system is stat3-mediated.
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stem cell factor restores Hepatocyte Proliferation in il 6 knockout mice following 70 hepatectomy
Journal of Clinical Investigation, 2003Co-Authors: Xiaodan Ren, Cory M. Hogaboam, Audra Carpenter, Lisa M. CollettiAbstract:Stem cell factor (SCF) is a molecule with known proliferative effects on hematopoietic cells. More recent studies suggest that this molecule may also have effects on cellular differentiation and Proliferation in other types of cells. The current investigations demonstrate that there is a large reservoir of SCF in the liver, that hepatic SCF levels change dramatically following partial hepatectomy in mice, and that SCF blockade, either by administration of anti-SCF antibodies or by using genetically altered, SCF-deficient mice, inhibits Hepatocyte Proliferation after partial hepatectomy; if SCF is replaced in the genetically SCF-deficient mice after partial hepatectomy, Hepatocyte Proliferation is restored to that seen in WT animals. Furthermore, SCF administration to IL-6 knockout mice also restores Hepatocyte Proliferation to normal. In vitro studies using primary mouse Hepatocytes demonstrate that SCF causes Hepatocyte Proliferation and is induced by IL-6 and that treatment with anti-SCF antibodies inhibits IL-6-induced Hepatocyte Proliferation. Further in vivo studies in IL-6 knockout mice demonstrate that SCF administration to these animals increases p-stat3 levels, suggesting that the SCF-induced increase in Hepatocyte Proliferation in this system is stat3-mediated.
Giovanna M. Ledda-columbano - One of the best experts on this subject based on the ideXlab platform.
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Expression of c-jun is not mandatory for mouse Hepatocyte Proliferation induced by two nuclear receptor ligands: TCPOBOP and T3
Journal of hepatology, 2011Co-Authors: Vera Piera Leoni, Giovanna M. Ledda-columbano, Monica Pibiri, Andrea Perra, Marta Anna Kowalik, Christian Saliba, Olì M. V. Grober, Maria Ravo, Alessandro Weisz, Joseph LockerAbstract:Background & Aims Mice lacking c-jun in the liver display impaired regeneration after partial hepatectomy (PH), and were reported to be more resistant to chemically-induced hepatocellular carcinoma (HCC). We investigated the role of c-jun in normal and preneoplastic Hepatocyte Proliferation induced by ligands of nuclear receptors, which cause liver hyperplasia in the absence of cell loss/death. Methods The effect of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) on Hepatocyte Proliferation was determined in c-jun conditional knockout ( c-jun Δli ) or in mouse liver where c-jun has been silenced. To study the role of c-jun in HCC development, c-jun Δli and WT mice were given diethylnitrosamine (DENA) followed by repeated injections of TCPOBOP. Results Hepatocyte Proliferation induced by TCPOBOP was associated with a stronger proliferative response and earlier S phase entry in c-jun Δli mice, compared to WT animals. Moreover, silencing of c-jun in the liver of CD-1 mice caused increased Hepatocyte Proliferation. A stronger Hepatocyte proliferative response of c-jun Δli mice was observed also following treatment with a ligand of thyroid hormone receptor. Finally, loss of c-jun did not inhibit the development of HCC induced by DENA and promoted by TCPOBOP. Conclusions (i) c-jun may, under certain conditions, negatively regulate Proliferation of normal Hepatocytes, (ii) c-jun is not an absolute requirement for DENA/TCPOBOP-induced HCC formation, suggesting that the therapeutic potential of c-jun/JNK inhibition in liver tumors might be impaired by an increased stimulation of cell growth due to blockade of the c-jun pathway.
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Induction of Hepatocyte Proliferation by retinoic acid
Carcinogenesis, 2004Co-Authors: Giovanna M. Ledda-columbano, Monica Pibiri, Francesca Molotzu, Costanza Cossu, L. Sanna, Gabriella Simbula, Andrea Perra, Amedeo ColumbanoAbstract:Retinoids have been shown to exert an anticarcinogenic effect through suppression of the cell cycle, induction of apoptosis and/or differentiation. In rat liver, in particular, retinoic acid has been shown to inhibit regeneration after partial hepatectomy, most probably through repression of the expression of c-fos and c-jun. Surprisingly enough, in spite of the proposed therapeutic effects of all-trans retinoic acid (tRA) no data are available on its effect on normal adult liver. Here, we show that tRA administration in the diet (150 mg/kg) increased DNA synthesis in mouse liver, at 1 and 2 weeks, with a return to control values at 4 weeks (labelling index was 16.5, 8.3 and 3.3%, respectively, versus control values of 1.4, 1.3 and 2.5%). Increase in mitotic index paralleled that of bromodeoxyuridine incorporation. Kinetic studies showed that entry into S phase began between 24 and 48 h, with a peak between 96 and 120 h. Histological observation of the liver and biochemical evaluation of the levels of serum glutamate-pyruvate transaminases did not reveal any evidence of cell death demonstrating that increased DNA synthesis was not due to tRA-induced liver damage and regeneration, but rather the consequence of a direct mitogenic effect. In addition, analysis of total hepatic DNA content after a 7-day treatment showed a significant increase in tRA-fed mice compared with controls (21.11 mg/100 g body wt in tRA-fed mice versus 15.67 mg/100 g body wt of controls). Hepatocyte Proliferation in tRA-fed mice was associated with increased hepatic levels of cyclin D1, E and A, and enhanced expression of the member of pRb family, p107. In conclusion, the results showed that tRA induces Hepatocyte Proliferation in the absence of cell death, similarly to other ligands of steroid/thyroid hormone nuclear receptor superfamily. The mitogenic effect of tRA cautions about its possible use for antitumoral purposes in liver carcinogenesis.
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In vivo Hepatocyte Proliferation is inducible through a TNF and IL-6-independent pathway.
Oncogene, 1998Co-Authors: Giovanna M. Ledda-columbano, M. Curto, R Piga, A.i. Zedda, Marta Menegazzi, Claudia Sartori, Hisashi Shinozuka, H Bluethmann, Valeria Poli, Gennaro CilibertoAbstract:Recent studies in mice harboring a targeted disruption of genes encoding TNF receptor 1 (TNFR-1) or Interleukin 6 (IL-6) suggested a critical role for TNF and IL-6 in initiation of liver regeneration after 2/3 partial hepatectomy. However, Hepatocyte Proliferation can also occur following treatment with agents that do not induce tissue loss (primary mitogens). To determine whether the above cytokines could also be involved in mitogen-induced liver cell Proliferation, we studied the Hepatocyte proliferative response after treatment with primary mitogens in mice knock-out for TNFR-1 or IL-6. Our results showed no difference in the proliferative response of the liver between the wild type and the knock-out mice following treatment with the mitogens 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), or the peroxisome proliferator, ciprofibrate, suggesting that TNF or IL-6 may not play a major role in this type of Proliferation. Gel shift assay indicated that TCPOBOP-induced Hepatocyte Proliferation is not associated with activation of STAT3 transcription factor, a major target of IL-6 and other growth factors/cytokines. Our results thus indicate that Hepatocyte Proliferation can be induced by at least two different pathways; compensatory regeneration being TNF and IL-6-dependent, and mitogen-induced direct hyperplasia which does not require TNF or IL-6.
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Hepatocyte Proliferation induced by a single dose of a peroxisome proliferator.
The American journal of pathology, 1996Co-Authors: T Ohmura, Amedeo Columbano, Giovanna M. Ledda-columbano, R Piga, Joseph Locker, J. Glemba, Sikandar L. Katyal, Hisashi ShinozukaAbstract:In compensatory hyperplasia after partial hepatectomy or liver cell injury, Hepatocyte Proliferation is triggered by coordinated actions of growth factor such as Hepatocyte growth factor and transforming growth factor-alpha and -beta. Initiation of Hepatocyte DNA synthesis is preceded by the activation of the set of early growth response genes mediated by enhanced nuclear factor-kappa B binding to DNA. Using an experimental model to induce Hepatocyte DNA synthesis in vivo by a single dose of a peroxisome proliferator, which does not induce liver cell necrosis (direct hyperplasia), we investigated whether peroxisome proliferator-induced Hepatocyte Proliferation involved an induction of known growth factors, an activation of early growth response genes, and nuclear factor-kappa B. A single intragastric administration of 250 mg/kg BR931 (4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio-(N-beta-hydroxyethyl) acetamide) to male wistar rats induced a wave of Hepatocyte DNA synthesis starting after 12 hours and peaking at approximately 24 to 36 hours. The response was dose dependent. The treatment also induced the expression of the mRNA for the peroxisomal bifunctional enzyme, one of the peroxisome-related fatty acid beta-oxidation enzymes. Pretreatment of rats with dexamethasone (2 mg/kg) inhibited both Hepatocyte DNA synthesis and the induction of the peroxisomal bifunctional enzyme gene. Northern blot analyses of liver RNA during a period preceding the onset of DNA synthesis revealed no induction of Hepatocyte growth factor, transforming growth factor-alpha, or tumor necrosis factor-alpha mRNAs. No induction of early growth response genes, liver regeneration factor-1, or c-myc was detected. Furthermore, gel mobility shift assays showed no enhanced nuclear factor-kappa B binding to its DNA consensus sequence after BR931 treatment, whereas control studies demonstrated a distinct increase in binding after partial hepatectomy or lead nitrate treatment. The results suggest that peroxisome-proliferator-induced Hepatocyte Proliferation may be triggered by signal transduction pathways different from those after partial hepatectomy and that the binding of peroxisome proliferators to their nuclear receptors may play a role in stimulation of DNA synthesis and peroxisome Proliferation.
Joseph Locker - One of the best experts on this subject based on the ideXlab platform.
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Yap is crucial for CAR‐driven Hepatocyte Proliferation, but not for induction of drug metabolism genes in mice
Hepatology (Baltimore Md.), 2020Co-Authors: Bharat Bhushan, Satdarshan P.s. Monga, Shirish Paranjpe, Wendy M Mars, Laura Molina, Kelly Koral, John Stoops, Swati Banerjee, Anne Orr, Joseph LockerAbstract:Constitutive androstane receptor (CAR) agonists, such as TCPOBOP, are known to cause robust Hepatocyte Proliferation and hepatomegaly in mice along with induction of drug metabolism genes, without any associated liver injury. Yes-associated protein (Yap) is a key transcription regulator that tightly controls organ size including that of liver. Ours and other previous studies suggested increased nuclear localization and activation of Yap after TCPOBOP-treatment in mice and potential role of Yap in CAR-driven proliferative response. Here, we investigated a direct role of Yap in CAR-driven hepatomegaly and Hepatocyte Proliferation using Hepatocyte-specific Yap-KO mice. AAV8-TBG-CRE vector was injected to Yap-floxed mice for achieving Hepatocyte-specific Yap deletion followed by TCPOBOP-treatment. Yap deletion did not decrease protein expression of CAR or CAR-driven induction of drug metabolism genes (including Cyp2b10, Cyp2c55 and Ugt1a1). However, Yap deletion substantially reduced TCPOBOP-induced Hepatocyte Proliferation. TCPOBOP-driven cell cycle activation was disrupted in Yap-KO mice due to delayed (and decreased) induction of cyclin D1 and higher expression of p21, resulting in decreased phosphorylation of retinoblastoma (Rb) protein. Further, induction of other cyclins, which are sequentially involved in progression through cell cycle (including cyclin E1, A2 and B1) and important mitotic regulators (such as aurora B kinase and polo-like kinase 1) was remarkably reduced in Yap-KO mice. Microarray analysis revealed that 26% of TCPOBOP-responsive genes mainly related to Proliferation, but not to drug metabolism, were altered by Yap deletion. Yap regulated these Proliferation genes via alerting expression of Myc and Foxm1, two critical transcriptional regulators of CAR-mediated Hepatocyte Proliferation. Conclusion: Our study revealed an important role of Yap signaling in CAR-driven Hepatocyte Proliferation; however, CAR-driven induction of drug metabolism genes was independent of Yap.
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yap is crucial for car driven Hepatocyte Proliferation but not for induction of drug metabolism genes in mice
Hepatology, 2020Co-Authors: Bharat Bhushan, Satdarshan P.s. Monga, Shirish Paranjpe, Wendy M Mars, Laura Molina, Kelly Koral, John Stoops, Swati Banerjee, Anne Orr, Joseph LockerAbstract:Constitutive androstane receptor (CAR) agonists, such as TCPOBOP, are known to cause robust Hepatocyte Proliferation and hepatomegaly in mice along with induction of drug metabolism genes, without any associated liver injury. Yes-associated protein (Yap) is a key transcription regulator that tightly controls organ size including that of liver. Ours and other previous studies suggested increased nuclear localization and activation of Yap after TCPOBOP-treatment in mice and potential role of Yap in CAR-driven proliferative response. Here, we investigated a direct role of Yap in CAR-driven hepatomegaly and Hepatocyte Proliferation using Hepatocyte-specific Yap-KO mice. AAV8-TBG-CRE vector was injected to Yap-floxed mice for achieving Hepatocyte-specific Yap deletion followed by TCPOBOP-treatment. Yap deletion did not decrease protein expression of CAR or CAR-driven induction of drug metabolism genes (including Cyp2b10, Cyp2c55 and Ugt1a1). However, Yap deletion substantially reduced TCPOBOP-induced Hepatocyte Proliferation. TCPOBOP-driven cell cycle activation was disrupted in Yap-KO mice due to delayed (and decreased) induction of cyclin D1 and higher expression of p21, resulting in decreased phosphorylation of retinoblastoma (Rb) protein. Further, induction of other cyclins, which are sequentially involved in progression through cell cycle (including cyclin E1, A2 and B1) and important mitotic regulators (such as aurora B kinase and polo-like kinase 1) was remarkably reduced in Yap-KO mice. Microarray analysis revealed that 26% of TCPOBOP-responsive genes mainly related to Proliferation, but not to drug metabolism, were altered by Yap deletion. Yap regulated these Proliferation genes via alerting expression of Myc and Foxm1, two critical transcriptional regulators of CAR-mediated Hepatocyte Proliferation. Conclusion: Our study revealed an important role of Yap signaling in CAR-driven Hepatocyte Proliferation; however, CAR-driven induction of drug metabolism genes was independent of Yap.
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Expression of c-jun is not mandatory for mouse Hepatocyte Proliferation induced by two nuclear receptor ligands: TCPOBOP and T3
Journal of hepatology, 2011Co-Authors: Vera Piera Leoni, Giovanna M. Ledda-columbano, Monica Pibiri, Andrea Perra, Marta Anna Kowalik, Christian Saliba, Olì M. V. Grober, Maria Ravo, Alessandro Weisz, Joseph LockerAbstract:Background & Aims Mice lacking c-jun in the liver display impaired regeneration after partial hepatectomy (PH), and were reported to be more resistant to chemically-induced hepatocellular carcinoma (HCC). We investigated the role of c-jun in normal and preneoplastic Hepatocyte Proliferation induced by ligands of nuclear receptors, which cause liver hyperplasia in the absence of cell loss/death. Methods The effect of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) on Hepatocyte Proliferation was determined in c-jun conditional knockout ( c-jun Δli ) or in mouse liver where c-jun has been silenced. To study the role of c-jun in HCC development, c-jun Δli and WT mice were given diethylnitrosamine (DENA) followed by repeated injections of TCPOBOP. Results Hepatocyte Proliferation induced by TCPOBOP was associated with a stronger proliferative response and earlier S phase entry in c-jun Δli mice, compared to WT animals. Moreover, silencing of c-jun in the liver of CD-1 mice caused increased Hepatocyte Proliferation. A stronger Hepatocyte proliferative response of c-jun Δli mice was observed also following treatment with a ligand of thyroid hormone receptor. Finally, loss of c-jun did not inhibit the development of HCC induced by DENA and promoted by TCPOBOP. Conclusions (i) c-jun may, under certain conditions, negatively regulate Proliferation of normal Hepatocytes, (ii) c-jun is not an absolute requirement for DENA/TCPOBOP-induced HCC formation, suggesting that the therapeutic potential of c-jun/JNK inhibition in liver tumors might be impaired by an increased stimulation of cell growth due to blockade of the c-jun pathway.
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Hepatocyte Proliferation induced by a single dose of a peroxisome proliferator.
The American journal of pathology, 1996Co-Authors: T Ohmura, Amedeo Columbano, Giovanna M. Ledda-columbano, R Piga, Joseph Locker, J. Glemba, Sikandar L. Katyal, Hisashi ShinozukaAbstract:In compensatory hyperplasia after partial hepatectomy or liver cell injury, Hepatocyte Proliferation is triggered by coordinated actions of growth factor such as Hepatocyte growth factor and transforming growth factor-alpha and -beta. Initiation of Hepatocyte DNA synthesis is preceded by the activation of the set of early growth response genes mediated by enhanced nuclear factor-kappa B binding to DNA. Using an experimental model to induce Hepatocyte DNA synthesis in vivo by a single dose of a peroxisome proliferator, which does not induce liver cell necrosis (direct hyperplasia), we investigated whether peroxisome proliferator-induced Hepatocyte Proliferation involved an induction of known growth factors, an activation of early growth response genes, and nuclear factor-kappa B. A single intragastric administration of 250 mg/kg BR931 (4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio-(N-beta-hydroxyethyl) acetamide) to male wistar rats induced a wave of Hepatocyte DNA synthesis starting after 12 hours and peaking at approximately 24 to 36 hours. The response was dose dependent. The treatment also induced the expression of the mRNA for the peroxisomal bifunctional enzyme, one of the peroxisome-related fatty acid beta-oxidation enzymes. Pretreatment of rats with dexamethasone (2 mg/kg) inhibited both Hepatocyte DNA synthesis and the induction of the peroxisomal bifunctional enzyme gene. Northern blot analyses of liver RNA during a period preceding the onset of DNA synthesis revealed no induction of Hepatocyte growth factor, transforming growth factor-alpha, or tumor necrosis factor-alpha mRNAs. No induction of early growth response genes, liver regeneration factor-1, or c-myc was detected. Furthermore, gel mobility shift assays showed no enhanced nuclear factor-kappa B binding to its DNA consensus sequence after BR931 treatment, whereas control studies demonstrated a distinct increase in binding after partial hepatectomy or lead nitrate treatment. The results suggest that peroxisome-proliferator-induced Hepatocyte Proliferation may be triggered by signal transduction pathways different from those after partial hepatectomy and that the binding of peroxisome proliferators to their nuclear receptors may play a role in stimulation of DNA synthesis and peroxisome Proliferation.