The CAR Nuclear Receptor and Hepatocyte Proliferation * #

Costa, Robert H.; Kalinchenko, Vladimir V.; Tan, Yongjun; Wang, I‐Ching

doi:10.1002/hep.20953

Cited by 34 publications

(36 citation statements)

References 50 publications

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“…Analysis of immediate early gene expression and cell cycle progression indicates a deficit in exiting from G 0 after partial hepatectomy in PBP mutant livers. We have also found that conditional PBP mutant mice do not respond to the cellproliferating response of mice to TCPOBOP, a well known primary mitogen (14,15). Impairment of the cell-proliferative response of Pbp ⌬Liv hepatocytes leads to enhanced proliferative expansion of an occasional PBP ϩ/ϩ hepatocyte present in these conditional mutant livers, in response to the PPAR␣ ligand Wy-14,643.…”

mentioning

confidence: 78%

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

Matsumoto

Jia

et al. 2007

Journal of Biological Chemistry

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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...

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mentioning

confidence: 78%

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

Matsumoto

Jia

et al. 2007

Journal of Biological Chemistry

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“…In liver, endogenous CAR resides in the cytoplasm of hepatocytes, and upon exposure to its agonist phenobarbital or 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), CAR translocates from the cytoplasm to the nucleus and triggers the transcription of target genes (43). Activation of CAR by TCPOBOP leads to profound hepatomegaly that involves both hypertrophic and hyperplastic responses (42,45). CAR agonists also translocate adenovirally expressed exogenous CAR from hepatocyte cytoplasm to the nucleus (46).…”

Section: Nuclear Receptors In Liver Regenerationmentioning

confidence: 99%

Med1 Subunit of the Mediator Complex in Nuclear Receptor-Regulated Energy Metabolism, Liver Regeneration, and Hepatocarcinogenesis

Jia

Viswakarma²,

Reddy³

2014

gene expr

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Several nuclear receptors regulate diverse metabolic functions that impact on critical biological processes, such as development, differentiation, cellular regeneration, and neoplastic conversion. In the liver, some members of the nuclear receptor family, such as peroxisome proliferator-activated receptors (PPARs), constitutive androstane receptor (CAR), farnesoid X receptor (FXR), liver X receptor (LXR), pregnane X receptor (PXR), glucocorticoid receptor (GR), and others, regulate energy homeostasis, the formation and excretion of bile acids, and detoxification of xenobiotics. Excess energy burning resulting from increases in fatty acid oxidation systems in liver generates reactive oxygen species, and the resulting oxidative damage influences liver regeneration and liver tumor development. These nuclear receptors are important sensors of exogenous activators as well as receptor-specific endogenous ligands. In this regard, gene knockout mouse models revealed that some lipid-metabolizing enzymes generate PPARα-activating ligands, while others such as ACOX1 (fatty acyl-CoA oxidase1) inactivate these endogenous PPARα activators. In the absence of ACOX1, the unmetabolized ACOX1 substrates cause sustained activation of PPARα, and the resulting increase in energy burning leads to hepatocarcinogenesis. Ligand-activated nuclear receptors recruit the multisubunit Mediator complex for RNA polymerase II-dependent gene transcription. Evidence indicates that the Med1 subunit of the Mediator is essential for PPARα, PPARγ, CAR, and GR signaling in liver. Med1 null hepatocytes fail to respond to PPARα activators in that these cells do not show induction of peroxisome proliferation and increases in fatty acid oxidation enzymes. Med1-deficient hepatocytes show no increase in cell proliferation and do not give rise to liver tumors. Identification of nuclear receptor-specific coactivators and Mediator subunits should further our understanding of the complexities of metabolic diseases associated with increased energy combustion in liver.

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“…Finally, CAR activation promotes hepatocyte proliferation and blocks apoptosis, and is essential for the tumorigenesis induced by its activators PB and TCPOBOP. The role of CAR in endobiotic and xenobiotics metabolism has clinical implications in disease prevention, drug-drug interactions, and the development of better drug treatments [27][28][29][30][31]. CAR is known to have naturally occurring alternatively spliced transcripts that encode proteins with altered ability to transactivate.…”

Section: Mini Reviewmentioning

confidence: 99%

Novel Orphan Nuclear Receptors-Coregulator Interactions Controlling Anti-Cancer Drug Metabolism

Gollamudi¹,

Gupta²,

Goel³

et al. 2008

CDM

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In recent years, it has become clear that drug metabolizing enzymes and efflux transporters are directly under the control of tissue-specific orphan receptors, mainly pregnenolone x-receptor (PXR), and constitutive androstene receptor (CAR), that coordinately regulate their transcription. The consequences of xenobiotic activation of these receptors leads to unpredictability of drug kinetics and in some cases drug pharmacodynamics. Since receptor specific co-regulators are critically involved in this process, this review serves to highlight important new advances in this area of research. Specifically, this review focuses on co-regulator interactions described for PXR and CAR and some models that provide an explanation for receptor activation and repression. PXR is basally repressed and is activated in a ligand and tissue specific manner through a complex shift in co-repressor (Silencing mediator of retinoid and thyroid receptor (SMRT) and nuclear receptor co-repressor (N-CoR)) and co-activator (Steroid receptor coactivator-1(SRC-1), PPAR and glucocorticoid receptor coactivator-1(PGC-1), Hepatocyte nuclear factor 4 (HNF-4)) interactions favoring activation. Other higher order complexes impinge on this shift and include small heterodimer partner (SHP) mediated inhibition of co-activators and still others involved in histone acetylation/deacetylation (e.g., SWI/SNF, HDACs). Similar interactions have been proposed for CAR and these will be discussed in detail. Finally, this review will focus on the implications of understanding receptor-co-regulator interactions with the eventual aim of assessing polymorphisms in this transcriptional complex as a method to normalize the effects of drug metabolism.

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The CAR Nuclear Receptor and Hepatocyte Proliferation * #

Cited by 34 publications

References 50 publications

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

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

Med1 Subunit of the Mediator Complex in Nuclear Receptor-Regulated Energy Metabolism, Liver Regeneration, and Hepatocarcinogenesis

Novel Orphan Nuclear Receptors-Coregulator Interactions Controlling Anti-Cancer Drug Metabolism

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