RGD Reference Report - Loss of Nrf2 in mice evokes a congenital intrahepatic shunt that alters hepatic oxygen and protein expression gradients and toxicity. - Rat Genome Database

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Loss of Nrf2 in mice evokes a congenital intrahepatic shunt that alters hepatic oxygen and protein expression gradients and toxicity.

Authors: Skoko, John J  Wakabayashi, Nobunao  Noda, Kentaro  Kimura, Shoko  Tobita, Kimimasa  Shigemura, Norihisa  Tsujita, Tadayuki  Yamamoto, Masayuki  Kensler, Thomas W 
Citation: Skoko JJ, etal., Toxicol Sci. 2014 Sep;141(1):112-9. doi: 10.1093/toxsci/kfu109. Epub 2014 Jun 12.
RGD ID: 14700900
Pubmed: PMID:24924401   (View Abstract at PubMed)
PMCID: PMC4271119   (View Article at PubMed Central)
DOI: DOI:10.1093/toxsci/kfu109   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Patent Ductus Venosus  ISOCyp2e1 (Mus musculus)14700900; 14700900 RGD 
Patent Ductus Venosus  IGINfe2l2 (Mus musculus)14700900 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cyp2e1  (cytochrome P450, family 2, subfamily e, polypeptide 1)

Genes (Mus musculus)
Cyp2e1  (cytochrome P450, family 2, subfamily e, polypeptide 1)

Genes (Homo sapiens)
CYP2E1  (cytochrome P450 family 2 subfamily E member 1)


Additional Information