Abstract
Liver regeneration can be impaired by permanent oxidative stress and activation of nuclear factor erythroid 2-related factor 2 (Nrf2), known to regulate the cellular antioxidant response, and has been shown to improve the process of liver regeneration. A variety of factors regulate hepatic tissue regeneration, among them augmenter of liver regeneration (ALR), attained great attention as being survival factors for the liver with proproliferative and antiapoptotic properties. Here we determined the Nrf2/antioxidant response element (ARE) regulated expression of ALR and show ALR as a target gene of Nrf2 in vitro and in vivo. The ALR promoter comprises an ARE binding site and, therefore, ALR expression can be induced by ARE-activator tertiary butylhydroquinone (tBHQ) in hepatoma cells and primary human hepatocytes (PHH). Promoter activity and expression of ALR were enhanced after cotransfection of Nrf2 compared with control and dominant negative mutant of Nrf2. Performing partial hepatectomy in livers from Nrf2+/+ mice compared with Nrf2-/- knock-out (KO) mice, we found increased expression of ALR in addition to known antioxidant ARE-regulated genes. Furthermore, we observed increased ALR expression in hepatitis B virus (HBV) compared with hepatitis C virus (HCV) positive hepatoma cells and PHH. Recently, it was demonstrated that HBV infection activates Nrf2 and, now, we add results showing increased ALR expression in liver samples from patients infected with HBV. ALR is regulated by Nrf2, acts as a liver regeneration and antioxidative protein and, therefore, links oxidative stress to hepatic regeneration to ensure survival of damaged cells.
Highlights
The liver is frequently challenged by metabolic overload, lipid accumulation, viruses or toxins which induce the formation of radicals and other reactive oxygen species (ROS) [1,2] and may lead to cellular damage
Previous studies exploring gene expression profiles induced by chemopreventive compounds such as phenethyl isothiocyanate [29] and sulforaphane [28], found enhanced augmenter of liver regeneration (ALR) mRNA expression in WT (Nrf2+/+) mice compared with KO (Nrf2–/–) mice
In line with this observation, we found ALR expression induced in hepatitis B virus (HBV)-infected, but not in hepatitis C virus (HCV)-infected, cells in vitro and in vivo (Figures 4, 5), which is in agreement with some recent findings reporting a HCVdependent inhibition of nuclear factor erythroid 2–related factor 2 (Nrf2)/antioxidant response element (ARE)
Summary
The liver is frequently challenged by metabolic overload, lipid accumulation, viruses or toxins which induce the formation of radicals and other reactive oxygen species (ROS) [1,2] and may lead to cellular damage. Crucial players in the defense of oxidative stress are antioxidant proteins and enzymes detoxifying electrophiles and radicals. It is well known that expression of these cytoprotective proteins is controlled by cis-acting regulatory elements in the promoters of these genes, the antioxidant responsive elements (AREs) [3]. It has been shown that ARE-driven gene expression is regulated mainly by the basic leucine zipper transcription factor nuclear factor erythroid 2–related factor 2 (Nrf2) [6], an important player in the defense against oxidative stress and a multiorgan protector in oxidative stressrelated diseases [7]. Activation of Nrf by electrophiles and radicals leads to dissociation of Nrf from Keap and to its translocation into the nucleus binding in partnership with other nuclear proteins to ARE sequences followed by activation of ARE-responsive genes [7]
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