Abstract
‘Augmenter of liver regeneration’ (ALR) (also known as hepatic stimulatory substance or hepatopoietin) was originally found to promote growth of hepatocytes in the regenerating or injured liver. ALR is expressed ubiquitously in all organs, and exclusively in hepatocytes in the liver. ALR, a survival factor for hepatocytes, exhibits significant homology with ERV1 (essential for respiration and viability) protein that is essential for the survival of the yeast, Saccharomyces cerevisiae. ALR comprises 198 to 205 amino acids (approximately 22 kDa), but is post-translationally modified to three high molecular weight species (approximately 38 to 42 kDa) found in hepatocytes. ALR is present in mitochondria, cytosol, endoplasmic reticulum, and nucleus. Mitochondrial ALR may be involved in oxidative phosphorylation, but also functions as sulfhydryl oxidase and cytochrome c reductase, and causes Fe/S maturation of proteins. ALR, secreted by hepatocytes, stimulates synthesis of TNF-α, IL-6, and nitric oxide in Kupffer cells via a G-protein coupled receptor. While the 22 kDa rat recombinant ALR does not stimulate DNA synthesis in hepatocytes, the short form (15 kDa) of human recombinant ALR was reported to be equipotent as or even stronger than TGF-α or HGF as a mitogen for hepatocytes. Altered serum ALR levels in certain pathological conditions suggest that it may be a diagnostic marker for liver injury/disease. Although ALR appears to have multiple functions, the knowledge of its role in various organs, including the liver, is extremely inadequate, and it is not known whether different ALR species have distinct functions. Future research should provide better understanding of the expression and functions of this enigmatic molecule.
Highlights
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
Upon testing whether Augmenter of liver regeneration’ (ALR) may exert similar effect, it was found that recombinant human ALR (rhALR) caused down-regulation of cytochrome P450 enzymes in human hepatocytes suggesting that this may be another mechanism of ALR’s role in liver regeneration [50]
We have found that LPS increases ALR release from cultured hepatocytes and circulating ALR levels increase in rats during endotoxemia
Summary
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. ALR and ERV1 are functionally interchangeable The mitochondrial presence of ALR and ERV1, necessary for the survival of hepatocytes and S. cerevisiae, respectively, led to the question whether these homologous proteins are functionally interchangeable Both the 15 kDa (short) and 22 kDa (long) cloned ALR proteins were found to prevent portacaval shunt-induced liver atrophy in dogs [19,20] suggesting that the antiatrophic/regenerative activity resides in the carboxy terminal sequence of the protein. Upon testing whether ALR may exert similar effect, it was found that rhALR caused down-regulation of cytochrome P450 enzymes in human hepatocytes suggesting that this may be another mechanism of ALR’s role in liver regeneration [50] Together, these findings lead to the postulate that ALR may support cell proliferation by influencing NFκB, c-Myc, polyamines, and cytochrome P-450. It is tempting to speculate that genetic deficiency of ALR may place human subjects at high risk to develop steatohepatitis (alcoholic and non-alcoholic), a topic of high clinical relevance
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