1. ¹Department of Biology, Institute of Cell Biology, ETH Zürich, Switzerland
2. ²Department of Internal Medicine I, University of Regensburg, Bavaria, Germany
3. ³Department of Medicine, University of California, San Francisco, CA, USA

Correspondence: Professor Dr S Werner, PhD, Department of Biology, Institute of Cell Biology, ETH Zürich, Hönggerberg, HPM D42, 8093 Zürich, Switzerland. E-mail: sabine.werner@cell.biol.ethz.ch

⁴Current address: Department of Hepatology and Gastroenterology, the Second Hospital of Shandong University, Jinan City, Shandong Province, China.

⁵Current address: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.

Received 17 March 2008; Revised 25 June 2008; Accepted 28 June 2008; Published online 4 August 2008.

Abstract

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 (CCl₄) 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 CCl₄ 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 CCl₄ 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.