Augmenter of liver regeneration: Essential for growth and beyond

• Published in: Cytokine & growth factor reviews 2019-02, Vol.45, p.65-80
• Main Authors: Ibrahim, Sara, Weiss, Thomas S.
• Format: Article
• Language: English
• Subjects: Augmenter of liver regeneration; Function; GFER; Isoforms; Location; Regulation
• ISSN: 1359-6101
• DOI: 10.1016/j.cytogfr.2018.12.003

•ALR is expressed in three isoforms (23, 21 and 15 kDa) in the brain, muscles, kidney and liver.•Long forms of ALR (lfALR, 23 and 21 kDa) are located in mitochondria and cytosol whereas short from ALR (sfALR, 15 kDa) is restricted to cytosol.•Detecting mutations in GFER gene (ALR) may be of importance in the diagnosis of critically ill infants and patients with mitochondrial disorders.•Both lfALR as well as sfALR possess diverse functions which might be attributed to their different subcellular locations and different structure.•Over-expressed sfALR activates different signaling pathways from the ones activated by exogenous applied recombinant ALR (rALR). Liver regeneration is a well-orchestrated process that is triggered by tissue loss due to trauma or surgical resection and by hepatocellular death induced by toxins or viral infections. Due to the central role of the liver for body homeostasis, intensive research was conducted to identify factors that might contribute to hepatic growth and regeneration. Using a model of partial hepatectomy several factors including cytokines and growth factors that regulate this process were discovered. Among them, a protein was identified to specifically support liver regeneration and therefore was named ALR (Augmenter of Liver Regeneration). ALR protein is encoded by GFER (growth factor erv1-like) gene and can be regulated by various stimuli. ALR is expressed in different tissues in three isoforms which are associated with multiple functions: The long forms of ALR were found in the inner-mitochondrial space (IMS) and the cytosol. Mitochondrial ALR (23 kDa) was shown to cooperate with Mia40 to insure adequate protein folding during import into IMS. On the other hand short form ALR, located mainly in the cytosol, was attributed with anti-apoptotic and anti-oxidative properties as well as its inflammation and metabolism modulating effects. Although a considerable amount of work has been devoted to summarizing the knowledge on ALR, an investigation of ALR expression in different organs (location, subcellular localization) as well as delineation between the isoforms and function of ALR is still missing. This review provides a comprehensive evaluation of ALR structure and expression of different ALR isoforms. Furthermore, we highlight the functional role of endogenously expressed and exogenously applied ALR, as well as an analysis of the clinical importance of ALR, with emphasis on liver disease and in vivo models, as well as