title: Transcription factor Nrf1 negatively regulates the cystine/glutamate transporter and lipid-metabolizing enzymes.
abstract: Liver-specific Nrf1 (NF-E2-p45-related factor 1) knockout mice develop nonalcoholic steatohepatitis. To identify postnatal mechanisms responsible for this phenotype, we generated an inducible liver-specific Nrf1 knockout mouse line using animals harboring an Nrf1(flox) allele and a rat CYP1A1-Cre transgene (Nrf1(flox/flox)::CYP1A1-Cre mice). Administration of 3-methylcholanthrene (3-MC) to these mice (Nrf1(flox/flox)::CYP1A1-Cre+3MC mice) resulted in loss of hepatic Nrf1 expression. The livers of mice lacking Nrf1 accumulated lipid, and the hepatic fatty acid (FA) composition in such animals differed significantly from that in the Nrf1(flox/flox)::CYP1A1-Cre control. This change was provoked by upregulation of several FA metabolism genes. Unexpectedly, we also found that the level of glutathione was increased dramatically in livers of Nrf1(flox/flox)::CYP1A1-Cre+3MC mice. While expression of glutathione biosynthetic enzymes was unchanged, xCT, a component of the cystine/glutamate antiporter system x(c)(-), was significantly upregulated in livers of Nrf1(flox/flox)::CYP1A1-Cre+3MC mice, suggesting that Nrf1 normally suppresses xCT. Thus, stress-inducible expression of xCT is a two-step process: under homeostatic conditions, Nrf1 effectively suppresses nonspecific transactivation of xCT, but when cells encounter severe oxidative/electrophilic stress, Nrf1 is displaced from an antioxidant response element (ARE) in the gene promoter while Nrf2 is recruited to the ARE. Thus, Nrf1 controls both the FA and the cystine/cysteine content of hepatocytes by participating in an elaborate regulatory network.
authors.affiliation: Division of Cancer Research, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Tsujita
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Vivian
authors.initials: V
authors.lastname: Peirce
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Liam
authors.initials: L
authors.lastname: Baird
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Matsuyama
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Misaki
authors.initials: M
authors.lastname: Takaku
authors.affiliation: Department of Pathology, Ninewells Hospital, Tayside NHS Trust, Dundee, Scotland, United Kingdom.
authors.forename: Shawn V
authors.initials: SV
authors.lastname: Walsh
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Julian L
authors.initials: JL
authors.lastname: Griffin
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Uruno
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan masiyamamoto@med.tohoku.ac.jp j.d.hayes@dundee.ac.uk.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Division of Cancer Research, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom masiyamamoto@med.tohoku.ac.jp j.d.hayes@dundee.ac.uk.
authors.forename: John D
authors.initials: JD
authors.lastname: Hayes
mesh_terms: D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism; D026922:Amino Acid Transport Systems, Acidic / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D003553:Cystine / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D044943:Fatty Acid Desaturases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051266:Nuclear Respiratory Factor 1 / Q000502:physiology*; D011485:Protein Binding; D051381:Rats; D018110:Receptors, Lipoprotein / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D015533:Transcriptional Activation; D014280:Triglycerides / Q000378:metabolism
chemical_list: D027182:Amino Acid Transport System y+; D026922:Amino Acid Transport Systems, Acidic; D003553:Cystine; D019363:Cytochrome P-450 CYP1A1; D044943:Fatty Acid Desaturases; D005978:Glutathione; D026502:LDL-Receptor Related Proteins; D051266:Nuclear Respiratory Factor 1; D018110:Receptors, Lipoprotein; D014280:Triglycerides; C495634:Nrf1 protein, mouse; C492255:Slc7a11 protein, mouse; C000723960:Slc7a11 protein, rat
references.citation: Free Radic Biol Med. 2010 Jan 15;48(2):357-71
references.pmid: 19914374
references.citation: Exp Toxicol Pathol. 1998 Sep;50(4-6):514-8
references.pmid: 9784032
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10158-63
references.pmid: 17548814
references.citation: Neurosurgery. 2013 Jan;72(1):33-41; discussion 41
references.pmid: 23096413
references.citation: Cancer Res. 2013 Mar 15;73(6):1855-66
references.pmid: 23319806
references.citation: J Biol Chem. 2011 Nov 11;286(45):39282-9
references.pmid: 21953459
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8
references.pmid: 12629218
references.citation: Cancer Lett. 2011 Dec 15;312(1):55-61
references.pmid: 21906871
references.citation: Mol Cell Biol. 2011 Nov;31(22):4500-12
references.pmid: 21911472
references.citation: Nat Commun. 2012 Jun 06;3:883
references.pmid: 22673910
references.citation: J Biol Chem. 2006 Jul 14;281(28):19676-87
references.pmid: 16687406
references.citation: Mol Cell Biol. 2012 Feb;32(4):808-16
references.pmid: 22158967
references.citation: J Biol Chem. 2002 Nov 22;277(47):44765-71
references.pmid: 12235164
references.citation: Cancer Lett. 1991 Jul 4;58(3):221-4
references.pmid: 1855197
references.citation: Br J Cancer. 2008 Aug 5;99(3):464-72
references.pmid: 18648370
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):4120-5
references.pmid: 15738389
references.citation: Hepatology. 2007 Jul;46(1):147-57
references.pmid: 17526026
references.citation: Mol Biosyst. 2008 Feb;4(2):135-47
references.pmid: 18213407
references.citation: Nat Protoc. 2006;1(6):3159-65
references.pmid: 17406579
references.citation: Environ Health Perspect. 2011 Jan;119(1):56-62
references.pmid: 20805060
references.citation: Arch Biochem Biophys. 2010 Dec 15;504(2):221-7
references.pmid: 20831858
references.citation: J Biol Chem. 2005 May 27;280(21):20340-8
references.pmid: 15790560
references.citation: J Biol Chem. 2001 Jun 8;276(23):19778-86
references.pmid: 11279066
references.citation: J Biol Chem. 1999 Mar 5;274(10):6443-52
references.pmid: 10037736
references.citation: Mol Cell Biol. 2013 Sep;33(17):3461-72
references.pmid: 23816881
references.citation: Redox Biol. 2013 Jan 19;1:183-9
references.pmid: 24024152
references.citation: Mech Dev. 2000 Oct;97(1-2):141-8
references.pmid: 11025215
references.citation: Environ Toxicol. 2014 Dec;29(12):1399-408
references.pmid: 23712962
references.citation: Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11488-92
references.pmid: 8265578
references.citation: Biochem J. 2009 Mar 1;418(2):293-310
references.pmid: 18990090
references.citation: Mol Cell Biol. 2012 Jul;32(14):2760-70
references.pmid: 22586274
references.citation: J Pharmacol Exp Ther. 2007 Jul;322(1):40-7
references.pmid: 17435107
references.citation: J Biol Chem. 2003 Jun 13;278(24):21592-600
references.pmid: 12682069
references.citation: J Biol Chem. 2007 Aug 24;282(34):24670-8
references.pmid: 17609210
references.citation: Cell. 2000 Dec 8;103(6):865-75
references.pmid: 11136972
references.citation: Mol Cell Biol. 2003 Jul;23(13):4673-86
references.pmid: 12808106
references.citation: Cancer Cell. 2011 Mar 8;19(3):387-400
references.pmid: 21397861
references.citation: Genes Cells. 2011 Jun;16(6):692-703
references.pmid: 21554501
references.citation: Anal Biochem. 1980 Jul 15;106(1):207-12
references.pmid: 7416462
references.citation: Mol Cell Biol. 1996 Nov;16(11):6083-95
references.pmid: 8887638
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Aug 15;871(2):174-81
references.pmid: 18458005
references.citation: Adv Enzyme Regul. 2006;46:113-40
references.pmid: 16887173
references.citation: Hepatology. 2014 Apr;59(4):1381-92
references.pmid: 24170703
references.citation: J Biol Chem. 2008 Nov 28;283(48):33554-62
references.pmid: 18826952
references.citation: Arterioscler Thromb Vasc Biol. 2013 Jul;33(7):1513-20
references.pmid: 23640498
references.citation: Gene. 2002 Jul 10;294(1-2):1-12
references.pmid: 12234662
references.citation: FEBS J. 2013 Aug;280(15):3609-20
references.pmid: 23702335
references.citation: Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11371-5
references.pmid: 8248256
references.citation: Biochem J. 2006 Nov 1;399(3):373-85
references.pmid: 16872277