The Nrf2 transcription factor protects from toxin-induced liver injury and fibrosis

• Published in: Laboratory investigation Vol. 88; no. 10; pp. 1068 - 1078
• Main Authors: Xu, Weihua, Hellerbrand, Claus, Köhler, Ulrike A, Bugnon, Philippe, Kan, Yuet-Wai, Werner, Sabine, Beyer, Tobias A
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2008; Nature Publishing; Nature Publishing Group
• Subjects: Animals; Biological and medical sciences; Biotechnology; Carbon Tetrachloride Poisoning - pathology; Carbon Tetrachloride Poisoning - physiopathology; Cytokines - metabolism; Female; Fundamental and applied biological sciences. Psychology; Inflammation - pathology; Inflammation - physiopathology; Investigative techniques, diagnostic techniques (general aspects); Laboratory Medicine; Liver Cirrhosis - chemically induced; Liver Cirrhosis - pathology; Liver Cirrhosis - physiopathology; Medical sciences; Medicine; Medicine & Public Health; Metabolic Detoxication, Phase I - physiology; Mice; Mice, Knockout; NF-E2-Related Factor 2 - physiology; Pathology; research-article; fibrosis; inflammation; cirrhosis; oxidative stress; ROS; Hepatic fibrosis; Biotechnology; Oxidative stress; Hepatic disease; Inflammation; Cirrhosis; Toxin; Signal transduction; Clinical biology; Digestive diseases; Lesion; Transcription factor; Protection
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.2008.75

The liver is frequently exposed to insults, including toxic chemicals and alcohol, viral infection or metabolic overload. Although it can fully regenerate after acute injury, chronic liver damage causes liver fibrosis and cirrhosis, which can result in complete liver failure. In this study, we demonstrate that the NF-E2-related factor 2 (Nrf2) transcription factor protects the liver from acute and chronic toxin-mediated damage. Repair of the liver injury that occurs after a single treatment with the hepatotoxin carbon tetrachloride (CCl 4 ) was severely delayed in Nrf2-deficient mice. The defect in repair was accompanied by an enhanced and prolonged inflammatory and profibrotic response. After long-term CCl 4 treatment, liver fibrosis was strongly aggravated in the Nrf2 knockout mice and inflammation was enhanced. We demonstrate that these abnormalities are at least in part due to the reduced expression of known and novel Nrf2 target genes in hepatocytes, which encode enzymes involved in the detoxification of CCl 4 and its metabolites. These results suggest that activation of Nrf2 may be a novel strategy to prevent or ameliorate toxin-induced liver injury and fibrosis.