Nrf2 Activates Augmenter of Liver Regeneration (ALR) via Antioxidant Response Element and Links Oxidative Stress to Liver Regeneration

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.

Augmenter of liver regeneration: A key protein in liver regeneration and pathophysiology

“…A similar property to that in ALR has been identified in yeast; knockouts of its homolog, ERV1, lead to the death of yeast . The ALR protein has been shown to be important for mitochondrial biogenesis and gene expression, protein import machinery of the mitochondria, checking oxidative stress, regeneration of liver, and maturation of liver progenitors …”

Dual regulation of transcription factor Nrf2 by Keap1 and by the combined actions of β-TrCP and GSK-3

“…In addition to the well-documented role of Nrf2 in orchestrating adaptation to oxidative stress, increasing evidence indicates that Nrf2 also contributes to cell growth and the repair of damaged tissue [42][43][44][45]. In this case, activation of Nrf2 is presumed to facilitate cell growth by: (1) increasing nutrient availability; (2) augmenting the levels of NADPH, ATP and metabolic intermediates required for synthesis of macromolecules; (3) increasing production of signalling molecules; (4) limiting inflammation.…”

Psychosocial-Stress, Liver Regeneration and Weight Gain: a Conspicuous Pathophysiological Triad

“…Recently, it has been reported that Nrf2 pathway has been shown to regulate the cellular antioxidant response and improve the process of liver regeneration. It was shown that Nrf2/antioxidant response element (ARE) system is an effective way to control ALR expression necessary for hepatic regeneration [20]. Another study showed that ROS-induced Nrf2 is capable of triggering transcription of proteins that play vital role in cell redox homeostasis function [52].…”

“…It has been reported that the absence of Nrf2 results in delayed liver regeneration after partial hepatectomy [54]. The Nrf2 regulates the expression of ALR which acts as antioxidative protein and plays an important role in liver regeneration to ensure the survival of the damaged cells [20]. Free Nrf2 translocate to the hepatic cell nucleus where it regulates the expression of several genes involved in cell proliferation (Fig.…”

“…The ALR has immunoregulatory and cytoprotective effects of liver injury [19]. The ALR stimulates synthesis of TNFα, IL6 and nitric oxide in Kupffer cells [18, 20] which play important roles in repairing processes. Previous studies regarding hepatic recovery following partial hepatectomy and liver injuries strongly describe the involvement of various active growth factors such as HGF [21, 22], TGF-α [16], tumor necrosis factor alpha (TNFα) and epidermal growth factor (EGF).…”