Alrp, a survival factor that controls the apoptotic process of regenerating liver after partial hepatectomy in rats

Abstract

Augmenter of Liver Regeneration (Alrp) enhances, through unknown mechanism/s, hepatocyte proliferation only when administered to partially hepatectomized (PH) rats. Liver resection, besides stimulating hepatocyte proliferation, induces reactive oxygen species (ROS), triggering apoptosis. To clarify the role of Alrp in the process of liver regeneration, hepatocyte proliferation, apoptosis, ROS-induced parameters and morphological findings of regenerating liver were studied from PH rats Alrp-treated for 72 h after the surgery. The same parameters, evaluated on regenerating liver from albumin-treated PH rats, were used as control. The results demonstrated that Alrp administration induces the anti-apoptotic gene expression, inhibits hepatocyte apoptosis and reduces ROS-induced cell damage. These and similar data from in vitro studies and the presence of 'Alrp homologous proteins' in viruses as well as in mammals (i) allow to hypothesize that Alrp activity/ies may not be exclusive for regenerating liver and (ii) suggest the use of Alrp in the treatment of oxidative stress-related diseases.

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

“…This indicates enhanced ROS-mediated apoptosis and that Nrf2 regulated gene expression can abate this process. ALR is one of these Nrf2 regulated genes able to reduce apoptosis, which is supported by a recent report demonstrating that ALR administration induces antiapoptotic gene expression, inhibits hepatocyte apoptosis and reduces ROS-induced cell damage in a rat model of partial hepatectomy (13). Enhanced oxidative stress in the Nrf2 KO model is responsible for an impairment of insulin/IGF signaling and subsequent inhibition of PI3K-Akt pathway, explaining increased apoptosis and reduced liver regeneration (8).…”

“…Within this study we present some evidence that ALR, in addition to known antioxidant genes, is a protein regulated in response to Nrf2 activation to address cellular oxidative stress. This is underlined by observations that ALR reduces cell damage and apoptosis upon oxidative stress (13,24) and also improves renal function by reducing the extent of tubular injury in a renal ischemia/reperfusion model in which injury is known to be mediated by oxidative stress (40).…”

“…(11). Liver regeneration is a process regulated by a variety of molecules of which ALR gains great attention because hepatotrophic ALR supports the process of liver regeneration after partial hepatectomy (12,13), and exerts beneficial effects in models of hepatic failure (14,15) and liver fibrosis (16). ALR is a member of the ALR/Erv1 protein family with a flavin adenine dinucleotide (FAD)-linked sulfhydryl oxidase activity and is found extracellularly as well as within the cytoplasm and in the mitochondrial innermembrane system (12,17,18).…”

Dynamic and Coordinated Regulation of KEAP1-NRF2-ARE and p53/p21 Signaling Pathways Is Associated with Acetaminophen Injury Responsive Liver Regeneration

“…The KEAP1-NRF2-ARE signaling pathway may regulate an adaptive response to protect against oxidative damage following APAP challenge. In addition, ALR was identified to promote liver regeneration after partial hepatectomy (Polimeno et al, 2011) and to augment hepatocyte proliferation when the regenerative process was primed (Francavilla et al, 1994). ALR may exhibit a beneficial effect via NRF2 pathway on compensatory liver regeneration following APAP-induced liver injury.…”

Wuzhi Tablet (Schisandra SphenantheraExtract) Protects against Acetaminophen-Induced Hepatotoxicity by Inhibition of CYP-Mediated Bioactivation and Regulation of NRF2-ARE and p53/p21 Pathways

“…ALR is identified to promote liver regeneration after partial hepatectomy and to augment hepatocyte proliferation (Polimeno et al, 2011). Recent studies have revealed that ALR is one of the ARE-regulated genes that can be induced by NRF2 activation (Dayoub et al, 2013).…”