title: A Txnrd1-dependent metabolic switch alters hepatic lipogenesis, glycogen storage, and detoxification.
abstract: Besides helping to maintain a reducing intracellular environment, the thioredoxin (Trx) system impacts bioenergetics and drug metabolism. We show that hepatocyte-specific disruption of Txnrd1, encoding Trx reductase-1 (TrxR1), causes a metabolic switch in which lipogenic genes are repressed and periportal hepatocytes become engorged with glycogen. These livers also overexpress machinery for biosynthesis of glutathione and conversion of glycogen into UDP-glucuronate; they stockpile glutathione-S-transferases and UDP-glucuronyl-transferases; and they overexpress xenobiotic exporters. This realigned metabolic profile suggested that the mutant hepatocytes might be preconditioned to more effectively detoxify certain xenobiotic challenges. Hepatocytes convert the pro-toxin acetaminophen (APAP, paracetamol) into cytotoxic N-acetyl-p-benzoquinone imine (NAPQI). APAP defenses include glucuronidation of APAP or glutathionylation of NAPQI, allowing removal by xenobiotic exporters. We found that NAPQI directly inactivates TrxR1, yet Txnrd1-null livers were resistant to APAP-induced hepatotoxicity. Txnrd1-null livers did not have more effective gene expression responses to APAP challenge; however, their constitutive metabolic state supported more robust GSH biosynthesis, glutathionylation, and glucuronidation systems. Following APAP challenge, this effectively sustained the GSH system and attenuated damage.
authors.affiliation: Department of Immunology and Infectious Disease, Montana State University, Bozeman, MT 59718, USA.
authors.forename: Sonya V
authors.initials: SV
authors.lastname: Iverson
authors.forename: Sofi
authors.initials: S
authors.lastname: Eriksson
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Xu
authors.forename: Justin R
authors.initials: JR
authors.lastname: Prigge
authors.forename: Emily A
authors.initials: EA
authors.lastname: Talago
authors.forename: Tesia A
authors.initials: TA
authors.lastname: Meade
authors.forename: Erin S
authors.initials: ES
authors.lastname: Meade
authors.forename: Mario R
authors.initials: MR
authors.lastname: Capecchi
authors.forename: Elias S J
authors.initials: ES
authors.lastname: Arnér
authors.forename: Edward E
authors.initials: EE
authors.lastname: Schmidt
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage; D000818:Animals; D016227:Benzoquinones / Q000008:administration & dosage; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism*; D006003:Glycogen / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007097:Imines / Q000008:administration & dosage; D008658:Inactivation, Metabolic / Q000235:genetics*; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D054481:Thioredoxin Reductase 1 / Q000235:genetics / Q000378:metabolism*; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016227:Benzoquinones; D007097:Imines; D000082:Acetaminophen; D013879:Thioredoxins; D006003:Glycogen; D054481:Thioredoxin Reductase 1; C516125:Txnrd1 protein, mouse; C028473:N-acetyl-4-benzoquinoneimine; D005978:Glutathione
keywords: 5,5′-dithiobis(2-nitrobenzoic acid); ALT; APAP; ATP-binding cassette subfamily C multidrug-resistance transporters; Abcc; Aox1; BSO; Bioenergetics; CYP; Cre; DTNB; DTT; Drug metabolism; EDTA; GSH; GSSG; GST; Gsr; H&E; KEGG; Kyoto Encyclopedia of Genes and Genomes; MS; N-acetyl-p-benzoquinone imine; N-acetylcysteine; NAC; NADPH-quinine oxidase; NAPQI; Nqo1; ROS; Redox biology; SDS; SDS-PAGE; SDS-polyacrylamide gel electrophoresis; SEM; SULT; Sec; Thioredoxin reductase; Trx; TrxR; Txnip; UGDH; UGT; acetaminophen (paracetamol); alanine transaminase; aldehyde oxidase-1; bacteriophage P1 cyclization recombinase; buthionine sulfoximine; cytochrome P450; dithiothreitol; ethylenediamine tetraacetic acid; glutathione reductase; glutathione-S-transferase; hematoxylin and eosin; kDa; kilo-Dalton; loxP; mass spectrometry; oxidized glutathione disulfide; p-APDG; p-APDGS; p-acetamidophenyl-β-D-glucronide; p-acetamidophenyl-β-D-glucronide sodium salt; reactive oxygen species; recognition sites for Cre; reduced glutathione; selenocysteine; sodium dodecyl sulfate; standard error of the mean; sulfotransferase; thioredoxin mRNA or protein; thioredoxin reducatse-1 gene; thioredoxin reductase mRNA or protein; thioredoxin-interacting protein; txnrd1; uridine diphosphate-glucose dehydrogenase; uridine diphosphate-glucuronate transferase