Nrf2, a transcription factor mainly involved in antioxidant defense, regulates the expression of ALR, Augmenter of Liver Regeneration

The liver is frequently challenged by so called metabolic overload, lipid accumulation, viruses or toxins, which induce the formation of reactive oxygen species (ROS). ROS can damage lipids, protein and DNA by peroxidation leading to complete degradation. A crucial player in the defense against oxidative stress is NF-E2-related factor 2 (Nrf2). The transcription factor Nrf2 is important for protecting cells against oxidative damage. It has been shown that Nrf2 binds to the antioxidant response element (ARE) controlling the expression of antioxidant proteins involved in the detoxification of harmful compounds. Additionally, Augmenter of Liver Regeneration (ALR) was reported to be upregulated in models of liver damage caused by oxidative stress. Recent micro array analysis demonstrated that Nrf2 regulates several cytoprotective proteins including ALR. Furthermore, promoter analysis of ALR predicts the presence of ARE, the potential binding site for Nrf2. Therefore, we aimed to verify whether Nrf2 is involved in the regulation of ALR expression. Treatment of primary human hepatocytes and HepG2 cells with tBHQ, a well known ARE-activator, induced mRNA and protein expression of ALR. Furthermore, the promoter activity of ALR was significantly induced after co-transfection of Nrf2 over control and dominant negative mutant of Nrf2 (dnNrf2). The functional impact of increased promoter activity after Nrf2-transfection was underlined by elevated mRNA and protein levels of ALR. In addition, we could show that ALR expression in livers from Nrf2-/- KO mice compared to Nrf2+/+ mice was attenuated during hepatic regeneration after a two-third hepatectomy. In conclusion, we demonstrated that the anti-oxidant transcription factor Nrf2 regulates the expression of ALR, and this regulation is mediated by activation of ARE. Thus, we speculate that ALR might play an important role as hepatotrophic factor against oxidative stress caused by different insults in the liver.