The role of liver regeneration-associated protein ALR, Augmenter of Liver Regeneration, in cholestatic liver diseases

It was in 1994 when the term “Augmenter of Liver Regeneration (ALR)” was first coined to describe a protein that augments the proliferative response of the liver after partial hepatectomy in rats and dogs. Since then extensive work has been attributed to identify the expression of ALR’s different isoforms and exploring their localization-dependent functions. In the human liver, ALR is expressed in hepatocytes and cholangiocytes. Specifically, the long forms of ALR (lfALR, 23 and 21 kDa) have been identified in the cytosol and mitochondria where it acts as a disulfide relay system coupled to the oxidoreductase Mia40 for facilitating protein import into mitochondria. Additionally, the short form of ALR (sfALR, 15 kDa) was detected solely in the cytosol with some reports suggesting its release into serum upon hepatic injury. Upon release, ALR binds to its receptor and activates different signaling pathways. Depending on its localization, the dual signaling pathways of sfALR have been investigated and were found to be differential in various pathological models for various liver injuries. Cholestasis represents pathophysiologic syndromes defined as an impaired bile flow from the liver due to, among others, gallstones, local tumors and the genetic deficiencies in bile acids exporters. Regardless of the cause, the accumulation of toxic bile acids leads to liver injury by initiating apoptosis, ER-stress, mitochondrial instability and inflammatory response due to activation of neutrophils and Kupffer cells. Therefore, the regulation of ALR expression by bile acids and cholestasis-related cytokines (IL1) have been investigated and found that under cholestatic conditions, ALR expression is attenuated due to the activation of SHP (Small Heterodimer Partner) by bile acids. Furthermore, IL1 release from activated Kupffer cells also leads to reduced ALR expression that could be attributed to reduced SP1 expression and diminished Egr-1 binding to its binding site within ALR promoter and therefore eliminating its transactivation action. Furthermore, due to the different etiologies of cholestasis and the possible progression into liver cirrhosis and liver failure, exploring potential therapeutic options for cholestasis might be of great clinical importance. Interestingly, high levels of cytosolic endogenous sfALR (15 kDa) protect hepatocytes from cholestatic injury by reducing bile acid synthesis as well as desensitizing hepatocytes to extrinsic-induced apoptosis by activating STAT3 (signal transducer and activator of transcription 3). Moreover, ALR expression is reduced in patients with cholestasis due to presumably high concentrations of bile acids and inflammatory cytokines. In addition, application of recombinant human ALR (rhALR, 15 kDa) contributes to liverprotection through reducing bile acid synthesis and intrinsic apoptosis (caused by accumulation of bile acids in hepatocytes) via activation of NFB (Nuclear Factor kappa-light-chain-enhancer' of activated B-cells