Augmenter of liver regeneration

Following the discovery that the liver possesses a remarkable ability to regenerate, pursuit to identify factors that are involved in this phenomenon led to the discovery of many mitogens, co-mitogens, and inhibitors. Among them was a protein initially named hepatic stimulatory substance or hepatopoietin and now commonly known as ‘Augmenter of liver regeneration’ (ALR). ALR was subsequently purified, and cloned in rat, mouse, and human. Both native and cloned ALR augment liver regeneration following partial hepatectomy and prevent pathology of portacaval shunt surgery in animal models. ALR is produced and secreted exclusively by hepatocytes in the liver and stimulates synthesis of TNF-α, IL-6, and nitric oxide in Kupffer cells via a G-protein coupled receptor. ALR may also exert actions on hepatocytes in an autocrine manner. Interestingly, intracellular ALR was found to be a survival factor as its depletion causes rapid mitochondrial dysfunction and apoptotic/necrotic death of hepatocytes. In this regard, ALR exhibits significant homology with ERV1 protein (essential for respiration and viability found in the yeast, Saccharomyces cerevisiae). Thus it is not a surprise that ALR is expressed ubiquitously in all organs, and may have tissue-specific functions. Furthermore, post-translational modification of the 22 kDa native ALR protein to three high molecular weight species (38 to 42 kDa), and presence of ALR in mitochondria, cytosol, endoplasmic reticulum, and nucleus indicate that ALR may play an important role in various physiological functions in a cell. Current evidence indicates that ALR may be involved in mitochondrial oxidative phosphorylation, reduction of cytochrome c, and in regulation of the activities of certain proteins by its sulfhydryl oxidase activity as well as by inducing Fe/S maturation of proteins. Thus, although ALR appears to have multiple functions, the knowledge of its roles in various organs, even in the liver, is very inadequate. In this arti