ArticleToxicological sciences : an official journal of the Society of Toxicology2014
Loss of Nrf2 in mice evokes a congenital intrahepatic shunt that alters hepatic oxygen and protein expression gradients and toxicity.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 32 citations in OpenAlex.
- Dual role of Nrf2 signaling in hepatocellular carcinoma: promoting development, immune evasion, and therapeutic challenges.Frontiers in immunology · 2024Review
- TRIB1 regulates liver regeneration by antagonizing the NRF2-mediated antioxidant response.Cell death & disease · 2023Article
- NRF2 and the Moirai: Life and Death Decisions on Cell Fates.Antioxidants & redox signaling · 2023Review
- Urine-based Detection of Congenital Portosystemic Shunt in C57BL/6 Mice.Function (Oxford, England) · 2023Article
- Enterohepatic Shunt-Driven Cholemia Predisposes to Liver Cancer.Gastroenterology · 2022Article
- The isoquinoline PRL-295 increases the thermostability of Keap1 and disrupts its interaction with Nrf2.iScience · 2022Article
- Nrf2 in Neoplastic and Non-Neoplastic Liver Diseases.Cancers · 2020Review
- Roles of Nrf2 in Protecting the Kidney from Oxidative Damage.International journal of molecular sciences · 2020Review
- Nrf2 in liver toxicology.Archives of pharmacal research · 2020Review
- Article
- Liver Zonation in Health and Disease: Hypoxia and Hypoxia-Inducible Transcription Factors as Concert Masters.International journal of molecular sciences · 2019Review
- Activation of Nrf2 signaling by natural products-can it alleviate diabetes?Biotechnology advances · 2018Review
- Nrf2 deletion from adipocytes, but not hepatocytes, potentiates systemic metabolic dysfunction after long-term high-fat diet-induced obesity in mice.American journal of physiology. Endocrinology and metabolism · 2018Article
- Metabolic zonation of the liver: The oxygen gradient revisited.Redox biology · 2017Review
- Dimethyl Fumarate and Monomethyl Fumarate Promote Post-Ischemic Recovery in Mice.Translational stroke research · 2016Article
- Generation of a New Model Rat: Nrf2 Knockout Rats Are Sensitive to Aflatoxin B1 Toxicity.Toxicological sciences : an official journal of the Society of Toxicology · 2016Article
- Keap1/Nrf2 pathway activation leads to a repressed hepatic gluconeogenic and lipogenic program in mice on a high-fat diet.Archives of biochemistry and biophysics · 2016Article
- Crosstalk between Nrf2 and Notch signaling.Free radical biology & medicine · 2015Review
- Regulation of Ahr signaling by Nrf2 during development: Effects of Nrf2a deficiency on PCB126 embryotoxicity in zebrafish (Danio rerio).Aquatic toxicology (Amsterdam, Netherlands) · 2015Article
- WNT-3A regulates an Axin1/NRF2 complex that regulates antioxidant metabolism in hepatocytes.Antioxidants & redox signaling · 2015Article
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Authors and funding
9 authors at 4 institutions in 2 countries.
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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.
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