Participation of nuclear factor (erythroid 2-related), factor 2 in ameliorating lithocholic acid-induced cholestatic liver injury in mice.
OBJECTIVE
Lithocholic acid (LCA), the most toxic bile acid, induces cholestatic liver injury in rodents. We previously showed that LCA activates the oxidative stress-responsive nuclear factor (erythroid-2 like), factor 2 (Nrf2) in cultured liver cells, triggering adaptive responses that reduce cell injury. In this study, we determined whether Nrf2 protects the liver against LCA-induced toxicity in vivo.


METHODS
Nrf2 disrupted (Nrf2(-/-) ) and wild-type mice were treated with LCA (125 mg·kg(-1) body weight) to induce liver injury. Levels of mRNA, protein and function of important Nrf2 target genes coupled with liver histology and injury biomarkers of mice were examined.


RESULTS
In 4 day LCA treatments, we observed a significantly higher hepatic induction of Nrf2 target, cytoprotective genes including thioredoxin reductase 1, glutamate cysteine ligase subunits, glutathione S-transferases, haeme oxygenase-1 and multidrug resistance-associated proteins 3 and 4 in the wild type as compared with the Nrf2(-/-) mice. Moreover, basal and LCA-induced hepatic glutathione and activities of glutathione S-transferases and thioredoxin reductases were higher in wild-type than in Nrf2(-/-) mice. This reduced production of cytoprotective genes against LCA toxicity rendered Nrf2(-/-) mice more susceptible to severe liver damage with the presence of multifocal liver necrosis, inflamed bile ducts and elevation of lipid peroxidation and liver injury biomarkers, such as alanine aminotransferase and alkaline phosphatase.


CONCLUSIONS
Nrf2 plays a crucial cytoprotective role against LCA-induced liver injury by orchestrating adaptive responses. The pharmacological potential of targeting liver Nrf2 in the management of cholestatic liver diseases is proposed.
Division of Clinical Pharmacology & Toxicology, Physiology and Experimental Medicine Program, Research Institute, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada.
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KP
Tan
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Wood
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Yang
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Ito
D000818:Animals; D001652:Bile Ducts / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D002780:Cholestasis, Intrahepatic / Q000473:pathology / Q000517:prevention & control*; D015227:Lipid Peroxidation; D008095:Lithocholic Acid / Q000633:toxicity*; D008099:Liver / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009336:Necrosis; D018384:Oxidative Stress; D012720:Severity of Illness Index
D015415:Biomarkers; D051267:NF-E2-Related Factor 2; D008095:Lithocholic Acid