title: Loss of Nrf2 in mice evokes a congenital intrahepatic shunt that alters hepatic oxygen and protein expression gradients and toxicity.
abstract: The transcription factor Nrf2 (Nfe2l2 nuclear factor, erythroid 2-like 2) regulates gene expression directly, controlling pharmacological and toxicological responses. These processes may also be influenced by the structure of the hepatic vasculature, which distributes blood flow through compartmentalized microenvironments to maintain organismal stability. Castings of the hepatic portal vasculature of albino C57BL/6J but not ICR Nrf2(-/-) mice revealed a congenital intrahepatic shunt that was present in two thirds of Nrf2-disrupted mice. This shunt directly connected the portal vein to the inferior vena cava and displayed characteristics of a patent ductus venosus. Immunohistochemistry revealed that Nrf2(-/-) mice with an intrahepatic shunt manifest changes to hepatic oxygen and protein expression gradients when compared with wild-type (WT) and non-shunted Nrf2(-/-) mice. Centrilobular hypoxia found in WT and Nrf2(-/-) mice without shunts was reduced in Nrf2(-/-) livers with a shunt. Hepatic protein expression of phosphoenolpyruvate carboxykinase (Pepck), normally confined to the periportal zone, exhibited both periportal and centrilobular zonal expression in livers from Nrf2(-/-) mice with an intrahepatic shunt. Centrilobular expression of Cytochrome P450 2E1 (Cyp2e1) was diminished in shunted Nrf2(-/-) livers compared with WT and Nrf2(-/-) livers without shunts. The intrahepatic shunt in Nrf2(-/-) mice was further found to diminish acetaminophen hepatoxicity compared with WT and Nrf2(-/-) non-shunted mice following a 6 h challenge with 250 mg/kg acetaminophen. The presence of an intrahepatic shunt influences several physiological and pathophysiological properties of Nrf2(-/-) mice through changes in blood flow, hepatic oxygenation, and protein expression that extent beyond loss of canonical transactivation of Nrf2 target genes.
authors.affiliation: Department of Pharmacology & Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 Department of Pharmacology and Molecular Sciences, School of Medicine, The Johns Hopkins University, Baltimore, Maryland 21205.
authors.forename: John J
authors.initials: JJ
authors.lastname: Skoko
authors.affiliation: Department of Pharmacology & Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
authors.forename: Nobunao
authors.initials: N
authors.lastname: Wakabayashi
authors.affiliation: Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Noda
authors.affiliation: Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
authors.forename: Shoko
authors.initials: S
authors.lastname: Kimura
authors.affiliation: Department of Developmental Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
authors.forename: Kimimasa
authors.initials: K
authors.lastname: Tobita
authors.affiliation: Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213.
authors.forename: Norihisa
authors.initials: N
authors.lastname: Shigemura
authors.affiliation: Division of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Tsujita
authors.affiliation: Division of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Pharmacology & Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 Department of Pharmacology and Molecular Sciences, School of Medicine, The Johns Hopkins University, Baltimore, Maryland 21205 tkensler@pitt.edu.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kensler
mesh_terms: D000082:Acetaminophen / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D001165:Arteriovenous Malformations / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D004195:Disease Models, Animal; D008099:Liver / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D008102:Liver Circulation / Q000235:genetics; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency* / Q000235:genetics; D010100:Oxygen / Q000378:metabolism*
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000082:Acetaminophen; D019392:Cytochrome P-450 CYP2E1; D010100:Oxygen
keywords: Nrf2; acetaminophen toxicity; intrahepatic shunt; liver zonation; portacaval shunt