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	Sustained glutathione deficiency interferes with the liver response to TNF and liver regeneration after partial hepatectomy in mice.


Kimberly J. Riehle1,2, Jamil Haque2, Ryan S. McMahan2, Terrance J. Kavanagh3, Nelson Fausto2 , and Jean S. Campbell2


1Department of Surgery, University of Washington, Seattle, WA
2Department of Pathology, University of Washington, Seattle, WA
3Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA




Enclosed:
   Text: 13 pages (including title page)
   Tables: none
   Figures: four



Short Title: Glutathione deficiency and liver regeneration








Correspondence and for reprint requests:

Jean S. Campbell, PhD
Department of Pathology
University of Washington
1959 NE Pacific Street
Box 357705
Seattle, WA   98195-7705
Phone: 206-616-4796
Fax: 206-616-1943
campjs@uw.edu

Abstract
Glutathione (GSH) is a critical intracellular anti-oxidant that is active in free radical scavenging and as a reducing equivalent in biological reactions. Recent studies have suggested that GSH can affect cellular function at the level of gene transcription as well, in particular by affecting NF-(B activation.  Additionally, increased or decreased GSH levels in vitro have been tied to increased or decreased hepatocyte proliferation, respectively. Here we investigated the effect of GSH on the liver�s response to TNF injection and 2/3 partial hepatectomy (PH), using mice deficient for the modifier subunit of glutamate-cysteine ligase (GCLM), the rate-limiting enzyme in de novo GSH synthesis.  We demonstrate that Gclm-/- mice have a delay in I(B( degradation after TNF injection, resulting in delayed NF-(B nuclear translocation.   These mice display profound deficiencies in GSH levels both before and during regeneration, and after PH, Gclm-/- mice have an overall delay in cell cycle progression, with slower DNA synthesis, mitosis, and expression of cell cycle proteins. Moreover, there is a delay in expression of downstream targets of NF-(B in the regenerating liver in Gclm-/- mice.   These data suggest that GSH may play a role in hepatic NF-(B activation in vivo, which is necessary for accurate timing of liver regeneration.

Introduction
	Glutathione (GSH) is a tripeptide of glutamate, cysteine, and glycine.  It is the most abundant non-protein thiol in the cell, and is present at 5-10mM in hepatocytes ADDIN EN.CITE <EndNote><Cite><Author>Forman</Author><Year>2009</Year><RecNum>44</RecNum><DisplayText>[1]</DisplayText><record><rec-number>44</rec-number><foreign-keys><key app="EN" db-id="rat9f9w9r2zx0iersdq5t95gv52dv02tfpze">44</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Forman, H. J.</author><author>Zhang, H.</author><author>Rinna, A.</author></authors></contributors><auth-address>School of Natural Science, University of California at Merced, P.O. Box 2039, Merced, CA 95344, USA. hjforman@gmail.com</auth-address><titles><title>Glutathione: overview of its protective roles, measurement, and biosynthesis</title><secondary-title>Mol Aspects Med</secondary-title></titles><periodical><full-title>Mol Aspects Med</full-title></periodical><pages>1-12</pages><volume>30</volume><number>1-2</number><edition>2008/09/18</edition><keywords><keyword>Animals</keyword><keyword>Glutamate-Cysteine Ligase/genetics/metabolism</keyword><keyword>Glutathione/*biosynthesis/chemistry/metabolism/*physiology</keyword><keyword>Humans</keyword><keyword>Molecular Structure</keyword></keywords><dates><year>2009</year><pub-dates><date>Feb-Apr</date></pub-dates></dates><isbn>1872-9452 (Electronic)&#xD;0098-2997 (Linking)</isbn><accession-num>18796312</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/18796312</url></related-urls></urls><custom2>2696075</custom2><electronic-resource-num>S0098-2997(08)00061-7 [pii]&#xD;10.1016/j.mam.2008.08.006</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_1" \o "Forman, 2009 #44" 1].  GSH scavenges reactive oxygen species (ROS) and acts as a cofactor in the metabolism of xenobiotics through reduction and conjugation reactions.  Several methods have been used in vivo and in vitro to study the effects of short-term GSH depletion on the hepatocyte cell cycle.    Previous experiments have demonstrated that GSH levels increase in proliferating hepatocytes ADDIN EN.CITE <EndNote><Cite><Author>Huang</Author><Year>1998</Year><RecNum>50</RecNum><DisplayText>[2]</DisplayText><record><rec-number>50</rec-number><foreign-keys><key app="EN" db-id="rat9f9w9r2zx0iersdq5t95gv52dv02tfpze">50</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Huang, Z. Z.</author><author>Li, H.</author><author>Cai, J.</author><author>Kuhlenkamp, J.</author><author>Kaplowitz, N.</author><author>Lu, S. C.</author></authors></contributors><auth-address>Center for Liver Disease Research, Department of Medicine, University of Southern California School of Medicine, Los Angeles 90033, USA.</auth-address><titles><title>Changes in glutathione homeostasis during liver regeneration in the rat</title><secondary-title>Hepatology</secondary-title></titles><periodical><full-title>Hepatology</full-title></periodical><pages>147-53</pages><volume>27</volume><number>1</number><edition>1998/01/13</edition><keywords><keyword>Animals</keyword><keyword>Cysteine/metabolism</keyword><keyword>DNA/biosynthesis</keyword><keyword>Glutathione/*metabolism</keyword><keyword>Hepatectomy/methods</keyword><keyword>Homeostasis/*physiology</keyword><keyword>Liver/metabolism</keyword><keyword>Liver Regeneration/*physiology</keyword><keyword>Male</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword></keywords><dates><year>1998</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0270-9139 (Print)&#xD;0270-9139 (Linking)</isbn><accession-num>9425930</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/9425930</url></related-urls></urls><electronic-resource-num>S0270913998000226 [pii]&#xD;10.1002/hep.510270123</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_2" \o "Huang, 1998 #50" 2], and short-term depletion of GSH by chemical inhibitors of glutamate cysteine ligase (GCL), the enzyme that catalyzes the rate limiting step in GSH biosynthesis, has been shown to delay hepatocyte proliferation in vitro ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_3" \o "Huang, 2001 #23" 3].   HYPERLINK \l "_ENREF_3" \o "Huang, 2001 #23" GSH levels are also elevated in human HCC ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_3" \o "Huang, 2001 #23" 3].  These data suggest a significant interaction between cellular GSH levels and cell proliferation in the liver.
	In addition to long-appreciated effects on cellular redox balance, recent studies demonstrate that GSH directly modifies proteins to affect their function.  Specifically, Reynaert et al found that post-translational S-glutathionylation of the inhibitory (B kinase (IKK), which normally functions to activate NF-(B, can directly affect its activity in vitro, and that oxidative stress directly leads to this modification ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_4" \o "Reynaert, 2006 #51" 4].   Glutathionylation of mitochondrial proteins such as ATP synthase appears to directly affect their activity ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_5" \o "Garcia, 2010 #65" 5].  Further, glutathionylation of the NF-(B subunit p65 in cultured hepatoma cells is dependent on redox status, such that oxidative stress leads to this modification, subsequent inhibition of NF-(B activation, and decreased cell survival ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_6" \o "Alisi, 2009 #66" 6].  In the liver, NF-(B functions in diverse processes, including regulating innate immunity, preventing apoptosis, and the development of cancer ADDIN EN.CITE <EndNote><Cite><Author>Chakraborty</Author><Year>2010</Year><RecNum>16</RecNum><DisplayText>[7]</DisplayText><record><rec-number>16</rec-number><foreign-keys><key app="EN" db-id="rat9f9w9r2zx0iersdq5t95gv52dv02tfpze">16</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chakraborty, J. B.</author><author>Mann, D. A.</author></authors></contributors><auth-address>Liver Research Group, Institute of Cellular Medicine, 4th Floor, Catherine Cookson Building, Medical School, Newcastle University, UK.</auth-address><titles><title>NF-kappaB signalling: embracing complexity to achieve translation</title><secondary-title>J Hepatol</secondary-title></titles><periodical><full-title>J Hepatol</full-title></periodical><pages>285-91</pages><volume>52</volume><number>2</number><edition>2009/12/22</edition><keywords><keyword>Animals</keyword><keyword>Humans</keyword><keyword>I-kappa B Kinase/chemistry/metabolism</keyword><keyword>Liver/*metabolism</keyword><keyword>Liver Diseases/genetics/metabolism</keyword><keyword>Models, Biological</keyword><keyword>NF-kappa B/chemistry/*metabolism</keyword><keyword>Protein Biosynthesis</keyword><keyword>Protein Subunits</keyword><keyword>Signal Transduction</keyword></keywords><dates><year>2010</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0168-8278 (Print)&#xD;0168-8278 (Linking)</isbn><accession-num>20022129</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/20022129</url></related-urls></urls><electronic-resource-num>S0168-8278(09)00737-5 [pii]&#xD;10.1016/j.jhep.2009.10.030</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_7" \o "Chakraborty, 2010 #16" 7], ADDIN EN.CITE <EndNote><Cite><Author>He</Author><Year>2011</Year><RecNum>18</RecNum><DisplayText>[8]</DisplayText><record><rec-number>18</rec-number><foreign-keys><key app="EN" db-id="rat9f9w9r2zx0iersdq5t95gv52dv02tfpze">18</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>He, G.</author><author>Karin, M.</author></authors></contributors><auth-address>Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California at San Diego, 9500 Gilman Drive MC 0723, La Jolla, CA 92093-0723, USA. ghe@isisph.com</auth-address><titles><title>NF-kappaB and STAT3 - key players in liver inflammation and cancer</title><secondary-title>Cell Res</secondary-title></titles><periodical><full-title>Cell Res</full-title></periodical><pages>159-68</pages><volume>21</volume><number>1</number><edition>2010/12/29</edition><keywords><keyword>Animals</keyword><keyword>Carcinoma, Hepatocellular/immunology/*metabolism</keyword><keyword>Hepatitis/complications</keyword><keyword>Inflammation/metabolism</keyword><keyword>Interleukin-6/metabolism</keyword><keyword>Liver/pathology</keyword><keyword>Liver Neoplasms/immunology/*metabolism</keyword><keyword>Mice</keyword><keyword>NF-kappa B/*metabolism/physiology</keyword><keyword>STAT3 Transcription Factor/*metabolism/physiology</keyword><keyword>Signal Transduction</keyword></keywords><dates><year>2011</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1748-7838 (Electronic)&#xD;1001-0602 (Linking)</isbn><accession-num>21187858</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/21187858</url></related-urls></urls><electronic-resource-num>cr2010183 [pii]&#xD;10.1038/cr.2010.183</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_8" \o "He, 2011 #18" 8], ADDIN EN.CITE <EndNote><Cite><Author>Yuan</Author><Year>2009</Year><RecNum>27</RecNum><DisplayText>[9]</DisplayText><record><rec-number>27</rec-number><foreign-keys><key app="EN" db-id="rat9f9w9r2zx0iersdq5t95gv52dv02tfpze">27</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yuan, L.</author><author>Kaplowitz, N.</author></authors></contributors><auth-address>Internal Medicine, University of Southern California, USA.</auth-address><titles><title>Glutathione in liver diseases and hepatotoxicity</title><secondary-title>Mol Aspects Med</secondary-title></titles><periodical><full-title>Mol Aspects Med</full-title></periodical><pages>29-41</pages><volume>30</volume><number>1-2</number><edition>2008/09/13</edition><keywords><keyword>Animals</keyword><keyword>Apoptosis/physiology</keyword><keyword>Glutathione/metabolism/*physiology</keyword><keyword>Humans</keyword><keyword>Liver Diseases/*metabolism</keyword><keyword>Mitochondria/metabolism</keyword><keyword>Oxidation-Reduction</keyword><keyword>Oxidative Stress/physiology</keyword><keyword>Signal Transduction/physiology</keyword></keywords><dates><year>2009</year><pub-dates><date>Feb-Apr</date></pub-dates></dates><isbn>1872-9452 (Electronic)&#xD;0098-2997 (Linking)</isbn><accession-num>18786561</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/18786561</url></related-urls></urls><electronic-resource-num>S0098-2997(08)00062-9 [pii]&#xD;10.1016/j.mam.2008.08.003</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_9" \o "Yuan, 2009 #27" 9].  HYPERLINK \l "_ENREF_10" \o "Fausto, 2006 #11"  HYPERLINK \l "_ENREF_11" \o "Riehle, 2011 #4" NF-(B has also been shown to have a key role in liver regeneration after partial hepatectomy (PH), both by preventing apoptosis and allowing cell cycle progression ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_10" \o "Chaisson, 2002 #15" 10], ADDIN EN.CITE <EndNote><Cite><Author>Plumpe</Author><Year>2000</Year><RecNum>56</RecNum><DisplayText>[11]</DisplayText><record><rec-number>56</rec-number><foreign-keys><key app="EN" db-id="rat9f9w9r2zx0iersdq5t95gv52dv02tfpze">56</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Plumpe, J.</author><author>Malek, N. P.</author><author>Bock, C. T.</author><author>Rakemann, T.</author><author>Manns, M. P.</author><author>Trautwein, C.</author></authors></contributors><auth-address>Department of Gastroenterology and Hepatology, Medizinische Hochschule, 30625 Hannover, Germany.</auth-address><titles><title>NF-kappaB determines between apoptosis and proliferation in hepatocytes during liver regeneration</title><secondary-title>Am J Physiol Gastrointest Liver Physiol</secondary-title></titles><periodical><full-title>Am J Physiol Gastrointest Liver Physiol</full-title></periodical><pages>G173-83</pages><volume>278</volume><number>1</number><edition>2000/01/25</edition><keywords><keyword>Animals</keyword><keyword>Apoptosis/drug effects/*physiology</keyword><keyword>Cell Cycle/drug effects</keyword><keyword>Cell Division/physiology</keyword><keyword>DNA/biosynthesis</keyword><keyword>Drug Resistance</keyword><keyword>Drug Synergism</keyword><keyword>Gliotoxin/pharmacology</keyword><keyword>Hepatectomy/methods</keyword><keyword>Humans</keyword><keyword>Liver/*cytology/drug effects/*physiology</keyword><keyword>Liver Regeneration/*physiology</keyword><keyword>Mice</keyword><keyword>NF-kappa B/antagonists &amp; inhibitors/*physiology</keyword><keyword>Tumor Cells, Cultured/drug effects</keyword><keyword>Tumor Necrosis Factor-alpha/pharmacology</keyword></keywords><dates><year>2000</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0193-1857 (Print)&#xD;0193-1857 (Linking)</isbn><accession-num>10644576</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/10644576</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_11" \o "Plumpe, 2000 #56" 11]. Thus, we were interested in studying the potential interplay between GSH levels, NF-(B activation in the liver, and hepatocyte proliferation after 2/3 PH.  	
	Prior work investigating the role of GSH in hepatocyte proliferation used in vivo chemical inhibition of GCL by D,L-buthionine sulfoximine (BSO) to temporarily decrease hepatic GSH content, though levels eventually increased to normal despite repeated doses of BSO ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_3" \o "Huang, 2001 #23" 3]. In order to achieve sustained GSH deficiency during liver regeneration, we took a genetic approach rather than a chemical approach.  GCL is composed of catalytic (GCLC) and modifier (GCLM) subunits ADDIN EN.CITE <EndNote><Cite><Author>Franklin</Author><Year>2009</Year><RecNum>45</RecNum><DisplayText>[12]</DisplayText><record><rec-number>45</rec-number><foreign-keys><key app="EN" db-id="rat9f9w9r2zx0iersdq5t95gv52dv02tfpze">45</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Franklin, C. C.</author><author>Backos, D. S.</author><author>Mohar, I.</author><author>White, C. C.</author><author>Forman, H. J.</author><author>Kavanagh, T. J.</author></authors></contributors><auth-address>Department of Pharmaceutical Sciences, University of Colorado Denver, Denver, CO 80262, USA. christopher.franklin@ucdenver.edu</auth-address><titles><title>Structure, function, and post-translational regulation of the catalytic and modifier subunits of glutamate cysteine ligase</title><secondary-title>Mol Aspects Med</secondary-title></titles><periodical><full-title>Mol Aspects Med</full-title></periodical><pages>86-98</pages><volume>30</volume><number>1-2</number><edition>2008/09/25</edition><keywords><keyword>Animals</keyword><keyword>Glutamate-Cysteine Ligase/*chemistry/metabolism/*physiology</keyword><keyword>Glutathione/metabolism</keyword><keyword>Humans</keyword><keyword>Models, Biological</keyword><keyword>Protein Processing, Post-Translational</keyword></keywords><dates><year>2009</year><pub-dates><date>Feb-Apr</date></pub-dates></dates><isbn>1872-9452 (Electronic)&#xD;0098-2997 (Linking)</isbn><accession-num>18812186</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/18812186</url></related-urls></urls><custom2>2714364</custom2><electronic-resource-num>S0098-2997(08)00063-0 [pii]&#xD;10.1016/j.mam.2008.08.009</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_12" \o "Franklin, 2009 #45" 12], ADDIN EN.CITE <EndNote><Cite><Author>Lu</Author><Year>2009</Year><RecNum>48</RecNum><DisplayText>[13]</DisplayText><record><rec-number>48</rec-number><foreign-keys><key app="EN" db-id="rat9f9w9r2zx0iersdq5t95gv52dv02tfpze">48</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lu, S. C.</author></authors></contributors><auth-address>Department of Medicine, Division of Gastroenterology and Liver Diseases, USC Research Center for Liver Diseases, USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine USC, Los Angeles, CA 90033, USA. shellylu@usc.edu</auth-address><titles><title>Regulation of glutathione synthesis</title><secondary-title>Mol Aspects Med</secondary-title></titles><periodical><full-title>Mol Aspects Med</full-title></periodical><pages>42-59</pages><volume>30</volume><number>1-2</number><edition>2008/07/08</edition><keywords><keyword>Animals</keyword><keyword>Glutamate-Cysteine Ligase/metabolism/physiology</keyword><keyword>Glutathione/metabolism/*physiology</keyword><keyword>Glutathione Synthase/metabolism/physiology</keyword><keyword>Humans</keyword><keyword>Models, Biological</keyword></keywords><dates><year>2009</year><pub-dates><date>Feb-Apr</date></pub-dates></dates><isbn>1872-9452 (Electronic)&#xD;0098-2997 (Linking)</isbn><accession-num>18601945</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/18601945</url></related-urls></urls><custom2>2704241</custom2><electronic-resource-num>S0098-2997(08)00050-2 [pii]&#xD;10.1016/j.mam.2008.05.005</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_13" \o "Lu, 2009 #48" 13].   Constitutive knockout of Gclc in mice is embryonic lethal ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_14" \o "Dalton, 2000 #62" 14], ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_15" \o "Yang, 2002 #46" 15], so we employed mice that lack Gclm ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_16" \o "McConnachie, 2007 #12" 16] in our studies.  While GCLM does not have any catalytic activity itself, it increases the efficiency of GCLC by lowering the Km for glutamate and ATP, and by decreasing feed back inhibition of GCL activity by GSH.  We have previously reported that Gclm-/- mice are particularly susceptible to acetaminophen-induced toxicity ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_16" \o "McConnachie, 2007 #12" 16], but resistant to the development of diet-induced steatohepatitis ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_17" \o "Haque, 2010 #2" 17].   Here we demonstrate that this model effectively maintains low GSH levels throughout liver regeneration, and are thus able to describe the consequences of compromised de novo GSH synthesis on this complex physiologic process. We show that GSH depletion interferes with the liver response to TNF in terms of NF-(B activation, and with the priming of liver regeneration.  GSH depletion also results in a significant delay in DNA replication after PH but does not cause a prolonged blockage of liver mass restitution. 
Materials and Methods
Animal Studies/Ethics Statement
All animal procedures were in accordance with the NIH Guide for the Use and Care of Laboratory Animals and were approved by the University of Washington Institutional Animal Care and Use Committee (protocol 2877-01).  Gclm+/- mice have been previously described  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_16" \o "McConnachie, 2007 #12" 16], and we used a breeding scheme in which heterozygous Gclm females were mated with heterozygous Gclm males, but only Gclm-/- (KO) and Gclm+/+ (wild type) mice were used for our experiments.  Murine TNF (25 (g/kg body weight, R&D Systems, Minneapolis, MN, USA) was injected intraperitoneally (IP) into 8 to 10 week old male Gclm-/- and wild type (wt) mice, and animals were sacrificed at the indicated time points after injection.  In a separate cohort of animals, 2/3 PH was performed on 8-10 week old male mice under isoflurane anesthesia following an overnight fast as described ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_18" \o "Riehle, 2008 #95" 18].  Mice were injected IP with bromodeoxyuridine (BrdU) (50 (g/g body weight, Roche Diagnostics, Indianapolis, IN, USA) 2 hours prior to sacrifice.  Livers were harvested after CO2 euthanasia and cardiac puncture, and weighed prior to sectioning and storage.

Immunoblotting
Whole liver homogenates were prepared using 1% Triton X-100 lysis buffer, quantified, and 40(g of total protein were subjected to SDS-PAGE and transferred to polyvinylidene difluoride membranes as described ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_18" \o "Riehle, 2008 #95" 18].   Immunoblotting was performed using standard procedures with the following antibodies: I(B( (Cell Signaling, Danvers, MA, USA), cyclin E (Upstate Biotechnologies, Billerica, MA, USA), or (-actin (Sigma, St. Louis, MO, USA).   

Immunohistochemistry
Harvested livers were immediately fixed either in 10% neutral buffered formalin or methacarn (60% methanol, 30% chloroform, 10% glacial acetic acid) and prepared for histological analysis.  Immunohistochemistry (IHC) for p65 (Santa Cruz Biotechnology, Santa Cruz, CA, USA), BrdU (Dako, Carpinteria, CA, USA), and activated caspase 3 (Cell Signaling) was performed using standard techniques.    To quantify hepatocyte prolferation, BrdU positive nuclei and HYPERLINK \l "_ENREF_21" \o "Campbell, 2006 #10"  mitotic figures were counted on slides cut from methacarn or formalin-fixed livers as described ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_19" \o "Campbell, 2006 #96" 19].  

RNA isolation and Real-time RT-PCR analysis
Total liver RNA was prepared using TRIzol (Invitrogen, Carlsbad, CA, USA), quantified, and 1 (g was reverse transcribed using the Retroscript kit (Ambion, Carlsbad, CA, USA) as described ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_18" \o "Riehle, 2008 #95" 18].    Real time RT-PCR was then performed for Tnf or Il6 using FAM-labeled primers and reagents (ABI, Carlsbad, CA, USA). 

Determination of GSH levels & Measurement of GCL activity
Total hepatic GSH levels were determined in Gclm-/- and wt mice before and after PH using a fluorogenic assay as described previously ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_16" \o "McConnachie, 2007 #12" 16].   Hepatic GCL activity was measured in liver lysates from Gclm-/- and wt mice before and after PH using a fluorogenic 96-well microtiter plate assay as described ADDIN EN.CITE <EndNote><Cite><Author>White</Author><Year>2003</Year><RecNum>38</RecNum><DisplayText>[20]</DisplayText><record><rec-number>38</rec-number><foreign-keys><key app="EN" db-id="rat9f9w9r2zx0iersdq5t95gv52dv02tfpze">38</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>White, C. C.</author><author>Viernes, H.</author><author>Krejsa, C. M.</author><author>Botta, D.</author><author>Kavanagh, T. J.</author></authors></contributors><auth-address>NIEHS Center Ecogenetics and Environmental Health, Department of Environmental Health, University of Washington, Seattle, WA 98195, USA.</auth-address><titles><title>Fluorescence-based microtiter plate assay for glutamate-cysteine ligase activity</title><secondary-title>Anal Biochem</secondary-title></titles><periodical><full-title>Anal Biochem</full-title></periodical><pages>175-80</pages><volume>318</volume><number>2</number><edition>2003/06/20</edition><keywords><keyword>Animals</keyword><keyword>Cells, Cultured</keyword><keyword>Fluorescence</keyword><keyword>Glutamate-Cysteine Ligase/*analysis/*metabolism</keyword><keyword>Hydrogen-Ion Concentration</keyword><keyword>Liver/cytology/enzymology</keyword><keyword>Liver Extracts</keyword><keyword>Mice</keyword><keyword>Microchemistry/methods</keyword><keyword>Time Factors</keyword></keywords><dates><year>2003</year><pub-dates><date>Jul 15</date></pub-dates></dates><isbn>0003-2697 (Print)&#xD;0003-2697 (Linking)</isbn><accession-num>12814619</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/12814619</url></related-urls></urls><electronic-resource-num>S000326970300143X [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_20" \o "White, 2003 #38" 20].

Enzyme Linked Immunosorbent Assay (ELISA)
Serum was obtained by cardiac puncture at the time of animal sacrifice, and IL-6 concentration therein was measured using a specific ELISA kit (R&D Systems) per the manufacturer�s instructions.

Fluorogenic Caspase Assay
	Caspase 3 activity was measured in 100 (g of protein using DEVD-7-amino-4-methyl coumarin (Enzo Life Sciences, Inc, Farmingdale, NY, USA) as a substrate ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_21" \o "Pierce, 2000 #42" 21].  Enzymatic assays and standard curves were generated in duplicate using a fluorescent plate reader (Packard Instruments, Palo Alto, CA, USA), with AML12 cells ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_22" \o "Wu, 1994 #55" 22] treated with Actinomycin D (Sigma-Aldrich) and TNF serving as positive controls ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_21" \o "Pierce, 2000 #42" 21].

Statistical analysis
Statistical analysis was done by non-parametric analysis using the Mann-Whitney U test with GraphPad Prism software (GraphPad for Science Inc, San Diego CA).  Data are presented as average +/- S.E.M., with p<0.05 considered statistically significant.  
Results
Gclm-/- mice as a model of severe and consistent GSH depletion before and after PH
Previous reports have demonstrated an increase in hepatic GSH levels in regenerating rat liver after PH ADDIN EN.CITE <EndNote><Cite><Author>Huang</Author><Year>1998</Year><RecNum>50</RecNum><DisplayText>[2]</DisplayText><record><rec-number>50</rec-number><foreign-keys><key app="EN" db-id="rat9f9w9r2zx0iersdq5t95gv52dv02tfpze">50</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Huang, Z. Z.</author><author>Li, H.</author><author>Cai, J.</author><author>Kuhlenkamp, J.</author><author>Kaplowitz, N.</author><author>Lu, S. C.</author></authors></contributors><auth-address>Center for Liver Disease Research, Department of Medicine, University of Southern California School of Medicine, Los Angeles 90033, USA.</auth-address><titles><title>Changes in glutathione homeostasis during liver regeneration in the rat</title><secondary-title>Hepatology</secondary-title></titles><periodical><full-title>Hepatology</full-title></periodical><pages>147-53</pages><volume>27</volume><number>1</number><edition>1998/01/13</edition><keywords><keyword>Animals</keyword><keyword>Cysteine/metabolism</keyword><keyword>DNA/biosynthesis</keyword><keyword>Glutathione/*metabolism</keyword><keyword>Hepatectomy/methods</keyword><keyword>Homeostasis/*physiology</keyword><keyword>Liver/metabolism</keyword><keyword>Liver Regeneration/*physiology</keyword><keyword>Male</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword></keywords><dates><year>1998</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0270-9139 (Print)&#xD;0270-9139 (Linking)</isbn><accession-num>9425930</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/9425930</url></related-urls></urls><electronic-resource-num>S0270913998000226 [pii]&#xD;10.1002/hep.510270123</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_2" \o "Huang, 1998 #50" 2].  As Gclm-/- mice lack the modulatory subunit of GCL, they lack the capacity to enzymatically regulate the catalytic subunit (GCLC) in response to changing cellular levels of the enzyme�s substrates, ATP and glutamate  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_16" \o "McConnachie, 2007 #12" 16].  With these feed-forward mechanisms disrupted and the subsequent non-inducible nature of GSH production, we hypothesized that Gclm-/- mice ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_16" \o "McConnachie, 2007 #12" 16] would not show an increase in GSH after 2/3 PH.  Consistent with the initial characterization of Gclm-/-mice, we observed that hepatic GSH levels in non-operated (non-op) mice are roughly 15% of wt levels (Figure 1A).   Similarly, GCL activity in Gclm-/- mice is less than 25% of that of wt mice (Figure 1B). We then measured hepatic GSH levels and GCL activity in wt and Gclm-/- mice after PH, and found that Gclm-/- mice maintained these low baseline GSH levels and GCL activity during liver regeneration.  Conversely, wt mice have a two-fold increase in whole liver GSH levels during the early phase of regeneration.   These data validate our use of Gclm-/- mice as a robust model of the effects of GSH deficiency on the regenerating liver.
Abnormal NF-(B activation after TNF injection into Gclm-/- mice
Recent studies have demonstrated that GSH can alter protein function directly ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_4" \o "Reynaert, 2006 #51" 4].  One protein that is altered in this way is IKK(, which normally functions to phosphorylate I(B(, thus allowing NF-(B to translocate to the nucleus to effect gene transcription ADDIN EN.CITE <EndNote><Cite><Author>Chakraborty</Author><Year>2010</Year><RecNum>16</RecNum><DisplayText>[7]</DisplayText><record><rec-number>16</rec-number><foreign-keys><key app="EN" db-id="rat9f9w9r2zx0iersdq5t95gv52dv02tfpze">16</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chakraborty, J. B.</author><author>Mann, D. A.</author></authors></contributors><auth-address>Liver Research Group, Institute of Cellular Medicine, 4th Floor, Catherine Cookson Building, Medical School, Newcastle University, UK.</auth-address><titles><title>NF-kappaB signalling: embracing complexity to achieve translation</title><secondary-title>J Hepatol</secondary-title></titles><periodical><full-title>J Hepatol</full-title></periodical><pages>285-91</pages><volume>52</volume><number>2</number><edition>2009/12/22</edition><keywords><keyword>Animals</keyword><keyword>Humans</keyword><keyword>I-kappa B Kinase/chemistry/metabolism</keyword><keyword>Liver/*metabolism</keyword><keyword>Liver Diseases/genetics/metabolism</keyword><keyword>Models, Biological</keyword><keyword>NF-kappa B/chemistry/*metabolism</keyword><keyword>Protein Biosynthesis</keyword><keyword>Protein Subunits</keyword><keyword>Signal Transduction</keyword></keywords><dates><year>2010</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0168-8278 (Print)&#xD;0168-8278 (Linking)</isbn><accession-num>20022129</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/20022129</url></related-urls></urls><electronic-resource-num>S0168-8278(09)00737-5 [pii]&#xD;10.1016/j.jhep.2009.10.030</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_7" \o "Chakraborty, 2010 #16" 7].  We thus hypothesized that Gclm-/- mice would have abnormal NF-(B activation in the liver.  We first chose to use TNF injection, a commonly used experimental method for activating NF-(B dependent transcription ADDIN EN.CITE <EndNote><Cite><Author>Streetz</Author><Year>2001</Year><RecNum>57</RecNum><DisplayText>[23]</DisplayText><record><rec-number>57</rec-number><foreign-keys><key app="EN" db-id="rat9f9w9r2zx0iersdq5t95gv52dv02tfpze">57</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Streetz, K. L.</author><author>Wustefeld, T.</author><author>Klein, C.</author><author>Manns, M. P.</author><author>Trautwein, C.</author></authors></contributors><auth-address>Dept. of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Germany.</auth-address><titles><title>Mediators of inflammation and acute phase response in the liver</title><secondary-title>Cell Mol Biol (Noisy-le-grand)</secondary-title></titles><periodical><full-title>Cell Mol Biol (Noisy-le-grand)</full-title></periodical><pages>661-73</pages><volume>47</volume><number>4</number><edition>2001/08/15</edition><keywords><keyword>Acute-Phase Reaction/*physiopathology</keyword><keyword>Animals</keyword><keyword>Antigens, CD/physiology</keyword><keyword>Apoptosis</keyword><keyword>Carbon Tetrachloride Poisoning/physiopathology</keyword><keyword>Cell Division</keyword><keyword>Cytokine Receptor gp130</keyword><keyword>Disease Models, Animal</keyword><keyword>Humans</keyword><keyword>Inflammation Mediators/*physiology</keyword><keyword>Interleukin-6/physiology</keyword><keyword>Liver/immunology/injuries/*physiopathology</keyword><keyword>Liver Regeneration/physiology</keyword><keyword>Macromolecular Substances</keyword><keyword>Membrane Glycoproteins/physiology</keyword><keyword>Signal Transduction</keyword><keyword>Tumor Necrosis Factor-alpha/physiology</keyword></keywords><dates><year>2001</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0145-5680 (Print)&#xD;0145-5680 (Linking)</isbn><accession-num>11502073</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/11502073</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_23" \o "Streetz, 2001 #57" 23]. Gclm-/- mice and wt littermates received IP injections of TNF and were sacrificed either 15 or 30 minutes after injection.  We first examined the kinetics of I(B( degradation, as this is an early step allowing subsequent NF-(B nuclear translocation and DNA binding.  Immunoblot analysis demonstrated similar levels of I(B( protein in non-injected wt and Gclm-/- mice.   Fifteen minutes after TNF injection, I(B( levels were equivalent in livers of wt and Gclm-/- mice (data not shown).   In wt mice, we observed that I(B( was almost completely absent from liver lysates by 30 minutes after TNF injection, in agreement with previously published data (Figure 2A).  In contrast, Gclm-/- mice had persistent hepatic I(B( at 30 minutes after TNF injection, indicating that its proteasomal degradation is delayed in mice with low levels of GSH.
The continued presence of I(B(, an inhibitor of NF-(B, in Gclm-/- mice suggested a delay or attenuation of NF-(B signaling after TNF injection.  To determine whether this delay altered TNF-induced NF-(B nuclear translocation, we examined the cellular distribution of NF-(B in hepatocytes by IHC.  In wt mice, we found strong nuclear staining for the NF-(B p65 subunit 15 minutes after TNF injection (Figure 2B), whereas Gclm-/- mice had an absence of nuclear staining at this time point, suggesting a defect in nuclear translocation of NF-(B in the setting of low GSH levels.   By 30 minutes after TNF injection, we found nuclear p65 localization in both genotypes (data not shown).
Following I(B( degradation, NF-(B activates gene transcription to affect a broad range of cellular functions.  To determine whether the delay in NF-(B nuclear translocation leads to a delay in NF-(B mediated gene transcription in Gclm-/- mice, we examined the expression of a known NF-(B target gene, Il6, after TNF injection by real-time PCR.  In wt mice there is an increase in Il6 expression at 15 and 30 minutes after injection (Figure 2C).  In Gclm-/- mice however, induction of Il6 expression 15 minutes after TNF injection is significantly blunted.  Our findings of decreased NF-(B activation after TNF injection in Gclm-/- mice lead us to hypothesize that liver regeneration, an NF-(B dependent process, would be defective in these mice.
Delayed DNA replication and hepatocyte proliferation in Gclm-/- mice after 2/3 PH.
Two thirds PH in rodents stimulates compensatory hyperplasia of the remaining hepatocytes wherein they exit G0, synchronously re-enter the cell cycle, divide once or twice and return to quiescence ADDIN EN.CITE <EndNote><Cite><Author>Fausto</Author><Year>2006</Year><RecNum>97</RecNum><DisplayText>[24]</DisplayText><record><rec-number>97</rec-number><foreign-keys><key app="EN" db-id="xw0a50zx7x5zz5eprx8pxr9qw0tf9vw5t02a">97</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fausto, N.</author><author>Campbell, J. S.</author><author>Riehle, K. J.</author></authors></contributors><auth-address>Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195-7470, USA. nfausto@u.washington.edu</auth-address><titles><title>Liver regeneration</title><secondary-title>Hepatology</secondary-title></titles><periodical><full-title>Hepatology</full-title></periodical><pages>S45-53</pages><volume>43</volume><number>2 Suppl 1</number><edition>2006/02/01</edition><keywords><keyword>Animals</keyword><keyword>Cell Cycle/drug effects</keyword><keyword>Cytokines/physiology</keyword><keyword>Growth Substances/physiology</keyword><keyword>Hepatectomy</keyword><keyword>Humans</keyword><keyword>Immunity, Innate</keyword><keyword>Liver/growth &amp; development/immunology/metabolism</keyword><keyword>Liver Regeneration/*physiology</keyword><keyword>Signal Transduction/physiology</keyword></keywords><dates><year>2006</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0270-9139 (Print)&#xD;0270-9139 (Linking)</isbn><accession-num>16447274</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/16447274</url></related-urls></urls><electronic-resource-num>10.1002/hep.20969</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_24" \o "Fausto, 2006 #97" 24].  In mice, the peak of the first round of DNA replication has been reported to occur around 36 hours after PH.  To determine whether hepatocyte proliferation is delayed in Gclm-/- mice following PH, we injected the thymidine analog BrdU IP 2 hours prior to sacrifice, and analyzed newly synthesized hepatocyte DNA by BrdU staining.  Consistent with previous data, wt mice have a peak of hepatocyte DNA replication at 36 hours that declines by 48 hours.  In Gclm-/- mice, however, DNA replication is relatively low at 36 hours after PH, but increases to peak at 48 hours after PH (Figure 3A), demonstrating an overall delay in DNA synthesis after PH when hepatic levels of GSH are reduced.
To determine whether the delay in hepatocyte proliferation in Gclm-/- mice extended beyond the S phase of the cell cycle, we assessed mitotic figures in hematoxylin and eosin stained liver sections after PH.   We observed the highest number of hepatocytes with mitotic nuclei at 40 hours after PH in wt mice.  Consistent with the delay in BrdU incorporation into proliferating hepatocytes in Gclm-/- mice, there were significantly fewer mitotic hepatocytes at this time point in Gclm-/- mice than in wt mice (Figure 3B), though the number of mitoses in Gclm-/- livers appeared to be increasing at 48 hours.  Similar to the decreased peak of BrdU labeling, Gclm-/- mice show a lower peak number of mitotic hepatocytes when compared to wt animals.
To determine whether the regenerative delay in Gclm-/- mice was present at the level of cell cycle control, we examined the expression of a late G1/S phase cell cycle protein, cyclin E, by immunoblot.  We found that its expression is decreased in Gclm-/- mice compared to wt mice at 36 hours after PH (Figure 3C).   Our data outlined above suggest that liver regeneration is delayed in Gclm-/- mice.  To determine whether a delay in the hepatocyte cell cycle also altered the liver to body weight ratios in these mice, we measured this parameter in Gclm-/- mice up to 6 days after PH and compared them to wt mice.  We did not observe a significant difference in liver to body weight ratios, suggesting that although liver regeneration is initially delayed in Gclm-/- mice, it does continue to completion (Figure 3D).

Increased apoptosis in Gclm-/- mice after PH.
	With their inability to up-regulate GSH levels in response to cellular stress, one might expect Gclm-/- mice to have more cellular injury after PH than do wt mice.  While apoptosis is not typically noted in the remnant wt liver after 2/3 PH ADDIN EN.CITE <EndNote><Cite><Author>Zorde-Khvalevsky</Author><Year>2009</Year><RecNum>60</RecNum><DisplayText>[25]</DisplayText><record><rec-number>60</rec-number><foreign-keys><key app="EN" db-id="rat9f9w9r2zx0iersdq5t95gv52dv02tfpze">60</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zorde-Khvalevsky, E.</author><author>Abramovitch, R.</author><author>Barash, H.</author><author>Spivak-Pohis, I.</author><author>Rivkin, L.</author><author>Rachmilewitz, J.</author><author>Galun, E.</author><author>Giladi, H.</author></authors></contributors><auth-address>Goldyne Savad Institute for Gene Therapy, Human Biology Research Center Hadassah-Hebrew University Medical Center, Jerusalem, Israel.</auth-address><titles><title>Toll-like receptor 3 signaling attenuates liver regeneration</title><secondary-title>Hepatology</secondary-title></titles><periodical><full-title>Hepatology</full-title></periodical><pages>198-206</pages><volume>50</volume><number>1</number><edition>2009/05/15</edition><keywords><keyword>Animals</keyword><keyword>Liver Regeneration/*physiology</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Signal Transduction</keyword><keyword>Toll-Like Receptor 3/*physiology</keyword></keywords><dates><year>2009</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1527-3350 (Electronic)&#xD;0270-9139 (Linking)</isbn><accession-num>19441101</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/19441101</url></related-urls></urls><electronic-resource-num>10.1002/hep.22973</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_25" \o "Zorde-Khvalevsky, 2009 #60" 25], several studies have linked inadequate antioxidant defenses to apoptosis in other systems ADDIN EN.CITE <EndNote><Cite><Author>Anathy</Author><Year>2009</Year><RecNum>31</RecNum><DisplayText>[26]</DisplayText><record><rec-number>31</rec-number><foreign-keys><key app="EN" db-id="rat9f9w9r2zx0iersdq5t95gv52dv02tfpze">31</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Anathy, V.</author><author>Aesif, S. W.</author><author>Guala, A. S.</author><author>Havermans, M.</author><author>Reynaert, N. L.</author><author>Ho, Y. S.</author><author>Budd, R. C.</author><author>Janssen-Heininger, Y. M.</author></authors></contributors><auth-address>Department of Pathology, University of Vermont, Burlington, VT 05405, USA.</auth-address><titles><title>Redox amplification of apoptosis by caspase-dependent cleavage of glutaredoxin 1 and S-glutathionylation of Fas</title><secondary-title>J Cell Biol</secondary-title></titles><periodical><full-title>J Cell Biol</full-title></periodical><pages>241-52</pages><volume>184</volume><number>2</number><edition>2009/01/28</edition><keywords><keyword>Animals</keyword><keyword>Antigens, CD95/*metabolism</keyword><keyword>*Apoptosis</keyword><keyword>Caspases/*metabolism</keyword><keyword>Cell Death</keyword><keyword>Epithelial Cells/metabolism</keyword><keyword>Fas Ligand Protein/metabolism</keyword><keyword>Glutaredoxins/*metabolism</keyword><keyword>Glutathione/*metabolism</keyword><keyword>Mice</keyword><keyword>Mice, Inbred Strains</keyword><keyword>Molecular Weight</keyword><keyword>NIH 3T3 Cells</keyword><keyword>Oxidation-Reduction</keyword><keyword>Reactive Oxygen Species/metabolism</keyword></keywords><dates><year>2009</year><pub-dates><date>Jan 26</date></pub-dates></dates><isbn>1540-8140 (Electronic)&#xD;0021-9525 (Linking)</isbn><accession-num>19171757</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/19171757</url></related-urls></urls><custom2>2654302</custom2><electronic-resource-num>jcb.200807019 [pii]&#xD;10.1083/jcb.200807019</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_26" \o "Anathy, 2009 #31" 26].  We thus used a fluorogenic caspase 3 activity assay to assess whether there is apoptosis in the livers of Gclm-/- mice after PH.    We confirmed the absence of detectable caspase 3 activity in wt liver lysates at 6, 24, and 48 hours after PH (Figure 4A).   In Gclm-/- mice, however, there was a small but consistent amount of caspase activity at 24 and 48 hours after PH, suggesting that without sufficient GSH there is an apoptotic response to PH that is not seen in other animals.  
	In order to determine in which Gclm-/- cell types this modest apoptotic activity after PH was occurring, we performed IHC for cleaved caspase 3.   We did not see any staining for cleaved caspase 3 in wt livers at 0, 24, or 36 hours after PH, but did see patchy cytosolic staining of hepatocytes in Gclm-/- livers 24 hours after PH (representative section shown in Figure 4B), with no significant staining in the non-parenchymal cells of any livers examined.   It should be noted that we did not see any evidence of liver necrosis in Gclm-/- or wt mice at any time point after PH (data not shown).   These data suggest that in the absence of adequate GSH, there is a small but consistent amount of hepatocyte apoptosis after PH, while apoptosis does not occur if GSH levels are normal.
Cytokine induction is delayed in Gclm-/- mice following PH. 
In order to determine whether the delay in liver regeneration seen in Gclm-/- mice could be related to defective NF-(B activation, we evaluated events known to be downstream of NF-(B after PH. In the regenerating liver, NF-(B activation in Kupffer cells leads to expression of Tnf, transactivation of the type 1 TNF receptor, and the release of IL-6, which has been shown to play several roles early in liver regeneration ADDIN EN.CITE <EndNote><Cite><Author>Fausto</Author><Year>2006</Year><RecNum>97</RecNum><DisplayText>[24]</DisplayText><record><rec-number>97</rec-number><foreign-keys><key app="EN" db-id="xw0a50zx7x5zz5eprx8pxr9qw0tf9vw5t02a">97</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fausto, N.</author><author>Campbell, J. S.</author><author>Riehle, K. J.</author></authors></contributors><auth-address>Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195-7470, USA. nfausto@u.washington.edu</auth-address><titles><title>Liver regeneration</title><secondary-title>Hepatology</secondary-title></titles><periodical><full-title>Hepatology</full-title></periodical><pages>S45-53</pages><volume>43</volume><number>2 Suppl 1</number><edition>2006/02/01</edition><keywords><keyword>Animals</keyword><keyword>Cell Cycle/drug effects</keyword><keyword>Cytokines/physiology</keyword><keyword>Growth Substances/physiology</keyword><keyword>Hepatectomy</keyword><keyword>Humans</keyword><keyword>Immunity, Innate</keyword><keyword>Liver/growth &amp; development/immunology/metabolism</keyword><keyword>Liver Regeneration/*physiology</keyword><keyword>Signal Transduction/physiology</keyword></keywords><dates><year>2006</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0270-9139 (Print)&#xD;0270-9139 (Linking)</isbn><accession-num>16447274</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/16447274</url></related-urls></urls><electronic-resource-num>10.1002/hep.20969</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_24" \o "Fausto, 2006 #97" 24]. HYPERLINK \l "_ENREF_12" \o "Chaisson, 2002 #15" We first measured expression of Tnf after PH, and found that the induction of this gene at 2 hours after PH in wt mice is deficient in Gclm-/- mice (Figure 4C), confirming lack of induction of an NF-(B target gene in the GSH-deficient regenerating liver.   Circulating levels of IL-6 typically peak within a few hours after PH, and consistent with previous findings, we found a marked increase in circulating IL-6 levels in wt mice at 4 hours after PH that decreases by 6 hours after surgery (Figure 4D).  In contrast, serum levels of IL-6 in Gclm-/- mice are lower than those of wt littermates at 4 hours after PH.  Six hours after PH IL-6 levels increase only slightly in Gclm-/- mice and are similar to the relatively low levels seen in wt mice at 6 hours after PH, suggesting that the release of IL-6 is attenuated in Gclm-/- mice, possibly related to deficient NF-(B activation.

Discussion
One of the early events in mammalian liver regeneration is the rapid activation of the NF-(B transcription factor ADDIN EN.CITE <EndNote><Cite><Author>Fausto</Author><Year>2006</Year><RecNum>97</RecNum><DisplayText>[24]</DisplayText><record><rec-number>97</rec-number><foreign-keys><key app="EN" db-id="xw0a50zx7x5zz5eprx8pxr9qw0tf9vw5t02a">97</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fausto, N.</author><author>Campbell, J. S.</author><author>Riehle, K. J.</author></authors></contributors><auth-address>Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195-7470, USA. nfausto@u.washington.edu</auth-address><titles><title>Liver regeneration</title><secondary-title>Hepatology</secondary-title></titles><periodical><full-title>Hepatology</full-title></periodical><pages>S45-53</pages><volume>43</volume><number>2 Suppl 1</number><edition>2006/02/01</edition><keywords><keyword>Animals</keyword><keyword>Cell Cycle/drug effects</keyword><keyword>Cytokines/physiology</keyword><keyword>Growth Substances/physiology</keyword><keyword>Hepatectomy</keyword><keyword>Humans</keyword><keyword>Immunity, Innate</keyword><keyword>Liver/growth &amp; development/immunology/metabolism</keyword><keyword>Liver Regeneration/*physiology</keyword><keyword>Signal Transduction/physiology</keyword></keywords><dates><year>2006</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0270-9139 (Print)&#xD;0270-9139 (Linking)</isbn><accession-num>16447274</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/16447274</url></related-urls></urls><electronic-resource-num>10.1002/hep.20969</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_24" \o "Fausto, 2006 #97" 24].  This process is initiated by signaling through the TNF receptor and activation of IKK, which phosphorylates the inhibitor of NF-(B, known as I(B( ADDIN EN.CITE <EndNote><Cite><Author>Chakraborty</Author><Year>2010</Year><RecNum>16</RecNum><DisplayText>[7]</DisplayText><record><rec-number>16</rec-number><foreign-keys><key app="EN" db-id="rat9f9w9r2zx0iersdq5t95gv52dv02tfpze">16</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chakraborty, J. B.</author><author>Mann, D. A.</author></authors></contributors><auth-address>Liver Research Group, Institute of Cellular Medicine, 4th Floor, Catherine Cookson Building, Medical School, Newcastle University, UK.</auth-address><titles><title>NF-kappaB signalling: embracing complexity to achieve translation</title><secondary-title>J Hepatol</secondary-title></titles><periodical><full-title>J Hepatol</full-title></periodical><pages>285-91</pages><volume>52</volume><number>2</number><edition>2009/12/22</edition><keywords><keyword>Animals</keyword><keyword>Humans</keyword><keyword>I-kappa B Kinase/chemistry/metabolism</keyword><keyword>Liver/*metabolism</keyword><keyword>Liver Diseases/genetics/metabolism</keyword><keyword>Models, Biological</keyword><keyword>NF-kappa B/chemistry/*metabolism</keyword><keyword>Protein Biosynthesis</keyword><keyword>Protein Subunits</keyword><keyword>Signal Transduction</keyword></keywords><dates><year>2010</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0168-8278 (Print)&#xD;0168-8278 (Linking)</isbn><accession-num>20022129</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/20022129</url></related-urls></urls><electronic-resource-num>S0168-8278(09)00737-5 [pii]&#xD;10.1016/j.jhep.2009.10.030</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_7" \o "Chakraborty, 2010 #16" 7].  The phosphorylation of I(B( leads to its ubiquitination and proteasomal degradation, which allows NF-(B to translocate to the nucleus and activate gene transcription. We show that in contrast to wt mice, GSH depleted mouse livers have persistent hepatic I(B( at 30 minutes after TNF injection, indicating that proteasomal degradation of I(B( is delayed and is possibly responsible for the inhibition of NF(B activation in these animals. Interestingly, TNF signaling has previously been shown to induce survival or apoptosis depending upon the redox status of the cell ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_21" \o "Pierce, 2000 #42" 21, HYPERLINK \l "_ENREF_27" \o "Han, 2009 #26" 27], ADDIN EN.CITE <EndNote><Cite ExcludeYear="1"><Author>Botta</Author><Year>2004</Year><RecNum>39</RecNum><DisplayText>[28]</DisplayText><record><rec-number>39</rec-number><foreign-keys><key app="EN" db-id="rat9f9w9r2zx0iersdq5t95gv52dv02tfpze">39</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Botta, D.</author><author>Franklin, C. C.</author><author>White, C. C.</author><author>Krejsa, C. M.</author><author>Dabrowski, M. J.</author><author>Pierce, R. H.</author><author>Fausto, N.</author><author>Kavanagh, T. J.</author></authors></contributors><auth-address>Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.</auth-address><titles><title>Glutamate-cysteine ligase attenuates TNF-induced mitochondrial injury and apoptosis</title><secondary-title>Free Radic Biol Med</secondary-title></titles><periodical><full-title>Free Radic Biol Med</full-title></periodical><pages>632-42</pages><volume>37</volume><number>5</number><edition>2004/08/04</edition><keywords><keyword>Animals</keyword><keyword>Apoptosis/*drug effects</keyword><keyword>Carcinoma, Hepatocellular</keyword><keyword>Cell Line, Tumor</keyword><keyword>Glutamate-Cysteine Ligase/*metabolism</keyword><keyword>Glutathione/metabolism</keyword><keyword>Humans</keyword><keyword>Liver Neoplasms</keyword><keyword>Mice</keyword><keyword>Mitochondria/drug effects/*pathology</keyword><keyword>Recombinant Proteins/metabolism</keyword><keyword>Transfection</keyword><keyword>Tumor Necrosis Factor-alpha/*toxicity</keyword></keywords><dates><year>2004</year><pub-dates><date>Sep 1</date></pub-dates></dates><isbn>0891-5849 (Print)&#xD;0891-5849 (Linking)</isbn><accession-num>15288121</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/15288121</url></related-urls></urls><electronic-resource-num>10.1016/j.freeradbiomed.2004.05.027&#xD;S0891584904004460 [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_28" \o "Botta, 2004 #39" 28].
Additionally, several recent reports have demonstrated that under certain conditions, GSH can form mixed disulfides with redox sensitive cysteine residues in proteins ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_29" \o "Aesif, 2009 #29" 29], ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_4" \o "Reynaert, 2006 #51" 4], ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_30" \o "Aesif, 2011 #30" 30].  This process, which is called S-glutathionylation, has been shown to alter protein function.  Several proteins in the NF-(B transcription factor pathway, including IKK, receptor-interacting protein (RIP), and the transcription factor components themselves, p50 and p65 ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_6" \o "Alisi, 2009 #66" 6] are among those that can be reversibly modified by GSH, thereby affecting their functions.  Another possibility is that lack of GSH increases oxidative stress and alters protein function directly. 
Given the decreased activation of NF-(B after TNF injection in Gclm-/- mice and the importance of NF-(B in liver regeneration, we expected that GSH depletion would lead to alterations in liver regeneration. Indeed, other investigators showed that temporary chemical depletion of GSH caused a delay in DNA replication after PH in rats ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_3" \o "Huang, 2001 #23" 3]. The effect of oxidative stress after PH has also been studied in Nrf2 KO mice ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_31" \o "Beyer, 2008 #61" 31].  These animals have a deficiency in detoxifying enzymes and transient insulin/IGF resistance after PH.  Oxidative stress in Nrf2 deficient animals causes steatosis and liver tumors, further demonstrating the crucial role of redox regulations in the liver.  We were interested in the effects of prolonged and severe GSH depletion on the sequence of events that lead to hepatocyte proliferation.  Gclm-/- mice lack the gene encoding the modifier subunit of GCL, and in the absence of GCLM, GCL enzyme function is compromised because of feedback inhibition of the enzyme by relatively low levels of GSH ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_16" \o "McConnachie, 2007 #12" 16], ADDIN EN.CITE <EndNote><Cite><Author>Lu</Author><Year>2009</Year><RecNum>48</RecNum><DisplayText>[13]</DisplayText><record><rec-number>48</rec-number><foreign-keys><key app="EN" db-id="rat9f9w9r2zx0iersdq5t95gv52dv02tfpze">48</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lu, S. C.</author></authors></contributors><auth-address>Department of Medicine, Division of Gastroenterology and Liver Diseases, USC Research Center for Liver Diseases, USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine USC, Los Angeles, CA 90033, USA. shellylu@usc.edu</auth-address><titles><title>Regulation of glutathione synthesis</title><secondary-title>Mol Aspects Med</secondary-title></titles><periodical><full-title>Mol Aspects Med</full-title></periodical><pages>42-59</pages><volume>30</volume><number>1-2</number><edition>2008/07/08</edition><keywords><keyword>Animals</keyword><keyword>Glutamate-Cysteine Ligase/metabolism/physiology</keyword><keyword>Glutathione/metabolism/*physiology</keyword><keyword>Glutathione Synthase/metabolism/physiology</keyword><keyword>Humans</keyword><keyword>Models, Biological</keyword></keywords><dates><year>2009</year><pub-dates><date>Feb-Apr</date></pub-dates></dates><isbn>1872-9452 (Electronic)&#xD;0098-2997 (Linking)</isbn><accession-num>18601945</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/18601945</url></related-urls></urls><custom2>2704241</custom2><electronic-resource-num>S0098-2997(08)00050-2 [pii]&#xD;10.1016/j.mam.2008.05.005</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_13" \o "Lu, 2009 #48" 13].  GCLM deficient mice are highly susceptible to the effects of acetaminophen, for instance, and conversely, animals that over-express GCLM are less sensitive to acetaminophen toxicity ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_16" \o "McConnachie, 2007 #12" 16], ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_32" \o "Botta, 2006 #47" 32].  Here we show that GSH is required for optimal release of IL-6 and activation of cell cycle components after PH, leading to a delay in DNA replication of approximately 8 hours in Gclm-/- mice.  Interestingly, after this delay, even with a persistent GSH deficit, completion of regeneration in Gclm-/- livers is similar to that of wt livers.   
The question of whether Gclm-/- mice have increased oxidative stress given their lack of glutathione is an interesting one.  The initial expectation was that Gclm-/- would have increased oxidative stress, but we have learned that these mice have significant compensation for their chronic lack of glutathione by up-regulating several antioxidant genes, including thioredoxin reductase and heme oxigenase  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_17" \o "Haque, 2010 #2" 17].   These data, in conjunction with evidence of decreased lipid peroxidation and catalase activity at baseline in Gclm-/- mice, lead us to believe that despite their inability to up-regulate glutathione in response to oxidative stress, other compensatory pathways actually give Gclm-/- mice enhanced anti-oxidant capabilities  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_16" \o "McConnachie, 2007 #12" 16, HYPERLINK \l "_ENREF_17" \o "Haque, 2010 #2" 17].   We thus do not believe that oxidative stress underlies the delay in liver regeneration in Gclm-/- mice.  
An interesting, albeit subtle, finding in the regenerating livers of Gclm-/- mice was a small amount of hepatocyte apoptosis beginning 24 hours after PH.   PH does not induce apoptosis in wt mice, unlike other models of regeneration, such as carbon tetrachloride injection ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_33" \o "Rio, 2008 #68" 33].   This finding is in accordance with other studies demonstrating that redox stress can induce apoptosis in hepatocytes ADDIN EN.CITE <EndNote><Cite><Author>Garcia-Ruiz</Author><Year>2007</Year><RecNum>69</RecNum><DisplayText>[34]</DisplayText><record><rec-number>69</rec-number><foreign-keys><key app="EN" db-id="rat9f9w9r2zx0iersdq5t95gv52dv02tfpze">69</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Garcia-Ruiz, C.</author><author>Fernandez-Checa, J. C.</author></authors></contributors><auth-address>Liver Unit, Hospital Clinic, C/Villarroel, Barcelona, Spain. checa229@yahoo.com</auth-address><titles><title>Redox regulation of hepatocyte apoptosis</title><secondary-title>J Gastroenterol Hepatol</secondary-title></titles><periodical><full-title>J Gastroenterol Hepatol</full-title></periodical><pages>S38-42</pages><volume>22 Suppl 1</volume><edition>2007/08/25</edition><keywords><keyword>Animals</keyword><keyword>Apoptosis/*physiology</keyword><keyword>Glutathione/metabolism</keyword><keyword>Hepatocytes/*physiology</keyword><keyword>Humans</keyword><keyword>Liver Diseases/*physiopathology</keyword><keyword>NF-kappa B/metabolism</keyword><keyword>*Oxidation-Reduction</keyword><keyword>Signal Transduction</keyword><keyword>Tumor Necrosis Factors/metabolism</keyword></keywords><dates><year>2007</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0815-9319 (Print)&#xD;0815-9319 (Linking)</isbn><accession-num>17567462</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17567462</url></related-urls></urls><electronic-resource-num>JGH4644 [pii]&#xD;10.1111/j.1440-1746.2006.04644.x</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_34" \o "Garcia-Ruiz, 2007 #69" 34], but we do not believe that this low level of cell death could account for the delay in hepatocyte proliferation in Gclm-/- mice.   Considering the profound GSH deficit in Gclm-/- mice, the phenotypes of delayed p65 activation after TNF injection and 8 hour delay in hepatocyte proliferation after PH may seem unimpressive.   In our experience, any such delay in regeneration is significant, as liver regeneration is simultaneously driven by dozens of pathways, which easily compensate for one another in most settings  ADDIN EN.CITE <EndNote><Cite><Author>Fausto</Author><Year>2006</Year><RecNum>97</RecNum><DisplayText>[24]</DisplayText><record><rec-number>97</rec-number><foreign-keys><key app="EN" db-id="xw0a50zx7x5zz5eprx8pxr9qw0tf9vw5t02a">97</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fausto, N.</author><author>Campbell, J. S.</author><author>Riehle, K. J.</author></authors></contributors><auth-address>Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195-7470, USA. nfausto@u.washington.edu</auth-address><titles><title>Liver regeneration</title><secondary-title>Hepatology</secondary-title></titles><periodical><full-title>Hepatology</full-title></periodical><pages>S45-53</pages><volume>43</volume><number>2 Suppl 1</number><edition>2006/02/01</edition><keywords><keyword>Animals</keyword><keyword>Cell Cycle/drug effects</keyword><keyword>Cytokines/physiology</keyword><keyword>Growth Substances/physiology</keyword><keyword>Hepatectomy</keyword><keyword>Humans</keyword><keyword>Immunity, Innate</keyword><keyword>Liver/growth &amp; development/immunology/metabolism</keyword><keyword>Liver Regeneration/*physiology</keyword><keyword>Signal Transduction/physiology</keyword></keywords><dates><year>2006</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0270-9139 (Print)&#xD;0270-9139 (Linking)</isbn><accession-num>16447274</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/16447274</url></related-urls></urls><electronic-resource-num>10.1002/hep.20969</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_24" \o "Fausto, 2006 #97" 24], ADDIN EN.CITE <EndNote><Cite><Author>Riehle</Author><Year>2011</Year><RecNum>94</RecNum><DisplayText>[35]</DisplayText><record><rec-number>94</rec-number><foreign-keys><key app="EN" db-id="xw0a50zx7x5zz5eprx8pxr9qw0tf9vw5t02a">94</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Riehle, K. J.</author><author>Dan, Y. Y.</author><author>Campbell, J. S.</author><author>Fausto, N.</author></authors></contributors><auth-address>Department of Surgery, University of Washington, Seattle, USA. kriehle@u.washington.edu</auth-address><titles><title>New concepts in liver regeneration</title><secondary-title>J Gastroenterol Hepatol</secondary-title></titles><periodical><full-title>J Gastroenterol Hepatol</full-title></periodical><pages>203-12</pages><volume>26 Suppl 1</volume><edition>2011/01/14</edition><keywords><keyword>Animals</keyword><keyword>*Cell Proliferation</keyword><keyword>Gene Expression Regulation</keyword><keyword>Hepatectomy</keyword><keyword>Hepatocytes/pathology/transplantation</keyword><keyword>Humans</keyword><keyword>Liver/*pathology/surgery</keyword><keyword>Liver Diseases/*pathology/surgery</keyword><keyword>*Liver Regeneration/genetics</keyword><keyword>Signal Transduction</keyword><keyword>Stem Cell Niche</keyword><keyword>Stem Cell Transplantation</keyword><keyword>Stem Cells/pathology</keyword></keywords><dates><year>2011</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1440-1746 (Electronic)&#xD;0815-9319 (Linking)</isbn><accession-num>21199532</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/21199532</url></related-urls></urls><custom2>3077908</custom2><electronic-resource-num>10.1111/j.1440-1746.2010.06539.x</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_35" \o "Riehle, 2011 #94" 35].  It should be noted that although Gclm-/- mice have compromised de novo synthesis of GSH, they do show up-regulation of other genes that may partially compensate for the low levels of GSH in these mice ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_17" \o "Haque, 2010 #2" 17, HYPERLINK \l "_ENREF_36" \o "Chen, 2012 #75" 36].   These include altered expression of pathways important for maintaining thiol redox status (including glutathione disulfide reductase, thioredoxin reductase, sulfiredoxin, and ribonucleotide reductase), which are known to be important in nucleotide synthesis. 
The effects of GSH depletion in the regenerating liver suggest that NF-(B activation is subject to regulation by glutathione in this setting.  Our results agree with those of Reynaert et al, which demonstrate the redox regulation of NF-(B in mouse alveolar type II epithelial cells in culture ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_4" \o "Reynaert, 2006 #51" 4].  Moreover, they showed that cys-179 of IKK is a target for activation by oxidative stress through S-glutathionylation.  Another group demonstrated that in cultured hepatoma cells, oxidative stress leads to glutathionylation of p65, and subsequent decrease in NF-(B activation  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_6" \o "Alisi, 2009 #66" 6].   If NF-(B is similarly regulated in the liver in vivo, the increase in GSH reported to occur in the regenerating liver would modulate IKK activity and/or other NF-(B components, leading to activation of the transcription factor.  We did not directly measure NF-(B activation itself in this setting, as it primarily occurs in Kupffer cells ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_10" \o "Chaisson, 2002 #15" 10], which comprise a small portion of the total liver cells.   Thus in the evaluation of whole liver homogenates or RNA, signaling events in Kupffer cells may be overwhelmed by the lack of such signals in hepatocytes.  
 In summary, in the present work we demonstrate an in vivo dependence on intact GSH levels for normal NF-(B activation after TNF injection.   Additionally, mice deficient in glutathione synthesis have impaired priming, delayed DNA synthesis, and low level apoptosis after PH.  This work may have implications for liver disease in humans, as relatively common genetic polymorphisms exist in both human GCLM and GCLC genes, and these have been shown to impact GCL expression, GSH synthesis, and risk for several diseases ADDIN EN.CITE <EndNote><Cite><Author>Franklin</Author><Year>2009</Year><RecNum>45</RecNum><DisplayText>[12]</DisplayText><record><rec-number>45</rec-number><foreign-keys><key app="EN" db-id="rat9f9w9r2zx0iersdq5t95gv52dv02tfpze">45</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Franklin, C. C.</author><author>Backos, D. S.</author><author>Mohar, I.</author><author>White, C. C.</author><author>Forman, H. J.</author><author>Kavanagh, T. J.</author></authors></contributors><auth-address>Department of Pharmaceutical Sciences, University of Colorado Denver, Denver, CO 80262, USA. christopher.franklin@ucdenver.edu</auth-address><titles><title>Structure, function, and post-translational regulation of the catalytic and modifier subunits of glutamate cysteine ligase</title><secondary-title>Mol Aspects Med</secondary-title></titles><periodical><full-title>Mol Aspects Med</full-title></periodical><pages>86-98</pages><volume>30</volume><number>1-2</number><edition>2008/09/25</edition><keywords><keyword>Animals</keyword><keyword>Glutamate-Cysteine Ligase/*chemistry/metabolism/*physiology</keyword><keyword>Glutathione/metabolism</keyword><keyword>Humans</keyword><keyword>Models, Biological</keyword><keyword>Protein Processing, Post-Translational</keyword></keywords><dates><year>2009</year><pub-dates><date>Feb-Apr</date></pub-dates></dates><isbn>1872-9452 (Electronic)&#xD;0098-2997 (Linking)</isbn><accession-num>18812186</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/18812186</url></related-urls></urls><custom2>2714364</custom2><electronic-resource-num>S0098-2997(08)00063-0 [pii]&#xD;10.1016/j.mam.2008.08.009</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_12" \o "Franklin, 2009 #45" 12], including non-alcoholic steatohepatitis ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_37" \o "Oliveira, 2010 #82" 37].

Acknowledgements
The authors thank Thomas Montine, Angela Wilson, Dianne Botta, Collin White, and B.J. Thompson for their input and technical assistance.  This work was supported by the Herbert Coe Foundation, the American College of Surgeons Foundation, the American Surgical Association Foundation (all to KJR), and NIH grants CA-23226 (to NF), CA-127228 (to NF), and CA-174131 (to JSC).


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Figure Legends
Figure 1. Gclm-/- mice are an adequate model of GSH depletion.  1A. GSH content in the livers of wt and Gclm-/- mice before and after PH.  * = p <0.05.  GSH, glutathione; PH, partial hepatectomy; wt, wild type; Gclm, glutamate cysteine ligase modifier subunit.  1B. GCL activity in the livers of Gclm-/- and wt mice before and after PH.  * = p <0.05.  GCL, glutamate cysteine ligase.  n=3-6 mice per genotype per time point.

Figure 2. Gclm-/- mice have delayed NF(B activation after TNF injection.   2A. Western blot demonstrating I(B( degradation 30 min after TNF injection.  TNF, tumor necrosis factor; n.s., non-specific band.   2B. IHC for p65 in wild type and Gclm-/- mice injected with TNF.  Images shown are at 40x magnification and are representative of 4-6 mice per group.  Scale bar is 100 microns.  2C. Real-time PCR for Il6 in whole liver RNA after TNF injection.  Wt, wild type; Il6, interleukin-6. n=3-6 mice per time point per genotype.

Figure 3. Delayed hepatocyte proliferation after PH in Gclm-/- mice.   3A. BrdU incorporation in hepatocytes after PH, presented as the percentage of positively staining hepatocytes in 3000 cells examined for each mouse.  * = p <0.05.  BrdU, bromodeoxyuridine; PH partial hepatectomy; wt, wild type.  3B. Hepatocyte mitotic counts after PH, presented as number of mitoses per 3000 hepatocytes examined.  * = p <0.05.   3C.  Western blot demonstrating cyclin E expression 36 hours after PH in wild type (+/+) and Gclm-/- (-/-) mice.  3D.  Liver weights expressed as a percentage of body weight 1, 2, and 6 days after PH in wt (wild type) and Gclm-/- mice.  n=3-6 mice per genotype per time point

Figure 4.  Elevated caspase activity and delayed cytokine induction in Gclm-/- mice after PH. 4A. Fluorogenic assay for activated caspase 3 performed on liver lysates at the indicated times after PH.  * = p<0.05. 4B. Representative section demonstrating IHC for cleaved caspase 3, 24 hours after PH in a Gclm-/- liver at 20x.  Inset is the hepatocyte designated by arrowhead, at 40x. 4C.  Real-time PCR for Tnf in whole liver RNA after PH.  * = p<0.05.  4D.  Circulating IL-6 levels after PH as measured by ELISA.  * = p <0.05. wt, wild type.  n=3-6 mice per genotype per time point.

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h�J�0Jjh�J�0JU,hN�h�J�B*CJOJQJ\�^JaJ1ph/h�0>h�J�6�B*CJOJQJ\�^JaJ1ph,h�0>h�J�B*CJOJQJ\�^JaJ1ph&h�J�B*CJOJQJ\�^JaJ1ph2h�`�h�J�6�B*CJH*OJQJ\�^JaJ1ph��/ ��=!�"�#��$��%�sD���y������K�	_ENREF_1sD���y������K�	_ENREF_2�	D<EndNote><Cite><Author>Huang</Author><Year>2001</Year><RecNum>23</RecNum><DisplayText>[3]</DisplayText><record><rec-number>23</rec-number><foreign-keys><key app="EN" db-id="rat9f9w9r2zx0iersdq5t95gv52dv02tfpze">23</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Huang, Z. Z.</author><author>Chen, C.</author><author>Zeng, Z.</author><author>Yang, H.</author><author>Oh, J.</author><author>Chen, L.</author><author>Lu, S. 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