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Augmenter of liver regeneration
Chandrashekhar R Gandhi
Fibrogenesis & Tissue Repair , 2012, DOI: 10.1186/1755-1536-5-10
Abstract: 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
Augmenter of Liver Regeneration (alr) Promotes Liver Outgrowth during Zebrafish Hepatogenesis  [PDF]
Yan Li, Muhammad Farooq, Donglai Sheng, Chanchal Chandramouli, Tian Lan, Nilesh K. Mahajan, R. Manjunatha Kini, Yunhan Hong, Thomas Lisowsky, Ruowen Ge
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030835
Abstract: Augmenter of Liver Regeneration (ALR) is a sulfhydryl oxidase carrying out fundamental functions facilitating protein disulfide bond formation. In mammals, it also functions as a hepatotrophic growth factor that specifically stimulates hepatocyte proliferation and promotes liver regeneration after liver damage or partial hepatectomy. Whether ALR also plays a role during vertebrate hepatogenesis is unknown. In this work, we investigated the function of alr in liver organogenesis in zebrafish model. We showed that alr is expressed in liver throughout hepatogenesis. Knockdown of alr through morpholino antisense oligonucleotide (MO) leads to suppression of liver outgrowth while overexpression of alr promotes liver growth. The small-liver phenotype in alr morphants results from a reduction of hepatocyte proliferation without affecting apoptosis. When expressed in cultured cells, zebrafish Alr exists as dimer and is localized in mitochondria as well as cytosol but not in nucleus or secreted outside of the cell. Similar to mammalian ALR, zebrafish Alr is a flavin-linked sulfhydryl oxidase and mutation of the conserved cysteine in the CxxC motif abolishes its enzymatic activity. Interestingly, overexpression of either wild type Alr or enzyme-inactive AlrC131S mutant promoted liver growth and rescued the liver growth defect of alr morphants. Nevertheless, alrC131S is less efficacious in both functions. Meantime, high doses of alr MOs lead to widespread developmental defects and early embryonic death in an alr sequence-dependent manner. These results suggest that alr promotes zebrafish liver outgrowth using mechanisms that are dependent as well as independent of its sulfhydryl oxidase activity. This is the first demonstration of a developmental role of alr in vertebrate. It exemplifies that a low-level sulfhydryl oxidase activity of Alr is essential for embryonic development and cellular survival. The dose-dependent and partial suppression of alr expression through MO-mediated knockdown allows the identification of its late developmental role in vertebrate liver organogenesis.
Expression of Augmenter of Liver Regeneration and Nuclear Faction-κB in Human Hepatocellular Carcinoma
Zhang Aimin,Shen Shiqiang
Journal of Animal and Veterinary Advances , 2012, DOI: 10.3923/javaa.2011.480.483
Abstract: To determine whether the levels of expression of the Augmenter of Liver Regeneration (ALR) and nuclear faction-κB(NF-κB) were assoiated with the clinicopathological features in human Hepatocellular Carcinoma (HCC). Gene expression was measured by using RT-PCR in the 30 human HCC tissues, matched adjacent tissues and 8 normal hepatic tissues. The clinicopathological data of all patients were also collected. Higher expression of ALR mRNA was observed in HCC tissues compared with normal liver tissue (p<0.05), it did not differ from the expression of matching non-neoplastic tissue in the same patient (p>0.05). Expression of both two genes were not found to be significantly associated with clinical/pathologic factors. (p>0.05). The expression of ALR mRNA in HCC tissues was positively correlated with NF-κB mRNA (r = 0.382, p<0.05). Up-regulation of ALR may play partial role of carcinogenesis through MAPK pathway in HCC.
Human hepatopoietin augmenter of liver regeneration — A hepatotrophic factor for liver regeneration, and its potential antihepatitis effectin vivo
Yang Xiaoming,Wang Aimin,Zhou Ping,Xie Ling,Wang Qingming,Wu Zuze,He Fuchu
Chinese Science Bulletin , 1998, DOI: 10.1007/BF02884641
Abstract: In addition to enhancing cell growth, adiministration of hALR achieved a significant improvement in reversing the lethality of rat hepatic failure when compared with that of control group; the elevation of cytcsolic enzymes was dramatically suppressed by exogenous hALR in CCl4-treated micein vivo andin vitro; histologically, hepatocytes around the central vein were necrotic, and the degree of hepatocyte necrosis in control mice was more prominent than that in the mice given 40 μg· kg-1 hALR 48 h after CCl4 administration. We also noted that hALR had a strong antihepatitis effectin vitro which was determined with primary cultured rat hepatocytes. These findings suggest that hALR protects the integrity of hepatocytes against severe hepatitis, and indicate that ALR may be an important regulator of liver regeneration and play a major role in liver injury repair. It proves ALR adminstration to be a useful treatment to accelerate liver regeneration and to prevent the onset of hepatitis or intrahepatic cholestasis induced by toxin.
Study on the CXXC Activity Motif of Human Augmenter of Liver Regeneration
人肝再生增强因子CXXC活性结构域的研究

PAN Yan,TONG Ming-hua,JU Gui-zhi,KONG Xiang-ping,
潘艳
,佟明华,鞠桂芝,孔祥平

中国生物工程杂志 , 2006,
Abstract: 人肝再生增强因子(human augmenter of liver regeneration,hALR)蛋白序列中有一段保守的Cys—Xaa—Xaa—Cys(CXXC)氨基酸序列,针对hALRp的CXXC结构,对hALR分别进行C65A和Q88c突变,表达、纯化突变体蛋白。体外检测hALRp和突变体的黄素腺嘌呤二核苷酸(flavin adenine dinucleotide,FAD)辅助的巯基氧化酶活性,hALR—FAD和hALRQ88C—FAD组与对照组比较有显著差异(P〈0.05),hALR,FAD和hALRQ88C—FAD组之间无差异;hALRC65A—FAD组与对照组比较无差异。结果显示,通过C65A突变将CXXC结构破坏后,该突变体的巯基氧化酶活性完全丧失;通过Q88c突变增加一个CXXC序列后,该突变体的巯基氧化酶活性较hALR—FAD未见明显增加;同时,FAD不仅是hALRp发挥巯基氧化酶活性必须的辅助因子,而且有助于hALRp突变体蛋白的复性。
Regulation of Signal Transduction and Role of Platelets in Liver Regeneration  [PDF]
Takeshi Nowatari,Kiyoshi Fukunaga,Nobuhiro Ohkohchi
International Journal of Hepatology , 2012, DOI: 10.1155/2012/542479
Abstract: Among all organs, the liver has a unique regeneration capability after sustaining injury or the loss of tissue that occurs mainly due to mitosis in the hepatocytes that are quiescent under normal conditions. Liver regeneration is induced through a cascade of various cytokines and growth factors, such as, tumor necrosis factor alpha, interleukin-6, hepatocyte growth factor, and insulin-like growth factor, which activate nuclear factor κB, signal transducer and activator of transcription 3, and phosphatidyl inositol 3-kinase signaling pathways. We previously reported that platelets can play important roles in liver regeneration through a direct effect on hepatocytes and collaborative effects with the nonparenchymal cells of the liver, including Kupffer cells and liver sinusoidal endothelial cells, which participate in liver regeneration through the production of various growth factors and cytokines. In this paper, the roles of platelets and nonparenchymal cells in liver regeneration, including the associated cytokines, growth factors, and signaling pathways, are described.
Cloning Differentially Expressed Genes by Suppression Subtractive Hybridization in Rat Liver Regeneration
应用抑制性消减杂交技术克隆大鼠肝再生过程中特异表达基因 Cloning Differentially Expressed Genes by Suppression Subtractive Hybridization in Rat Liver Regeneration

LI Yu-chang,XU Cun-shuan,ZHANG Yun-han,
李玉昌
,徐存拴,张云汉LI Yu-chang,XU Cun-shuan,ZHANG Yun-han

遗传 , 2002,
Abstract: The cDNA from rat regenerating liver tissue was used as the tester and that from normal liver was used as the driver. A highly efficient subtractive cDNA library was constructed by suppression subtractive hybridization(SSH). After screening, 31 clones from 50 clones which were derived from the cDNA library were inserted by 60-400 bp cDNA fragments. 24 cDNA fragments corresponded to known genes and 7 cDNA fragments were unknown sequences (GenBank accession number: BG447490-447496).
Regulation of Signal Transduction and Role of Platelets in Liver Regeneration  [PDF]
Takeshi Nowatari,Kiyoshi Fukunaga,Nobuhiro Ohkohchi
International Journal of Hepatology , 2012, DOI: 10.1155/2012/542479
Abstract: Among all organs, the liver has a unique regeneration capability after sustaining injury or the loss of tissue that occurs mainly due to mitosis in the hepatocytes that are quiescent under normal conditions. Liver regeneration is induced through a cascade of various cytokines and growth factors, such as, tumor necrosis factor alpha, interleukin-6, hepatocyte growth factor, and insulin-like growth factor, which activate nuclear factor κB, signal transducer and activator of transcription 3, and phosphatidyl inositol 3-kinase signaling pathways. We previously reported that platelets can play important roles in liver regeneration through a direct effect on hepatocytes and collaborative effects with the nonparenchymal cells of the liver, including Kupffer cells and liver sinusoidal endothelial cells, which participate in liver regeneration through the production of various growth factors and cytokines. In this paper, the roles of platelets and nonparenchymal cells in liver regeneration, including the associated cytokines, growth factors, and signaling pathways, are described. 1. Introduction Liver regeneration is a physiopathological phenomenon of quantitative recovery from the loss of liver mass to compensate for decreased hepatic volume and impaired function [1, 2]. Although numerous studies have shown that a variety of genes, cytokines, growth factors, and cells are involved in liver regeneration, the exact mechanism of regeneration and the interaction between hepatocytes and cytokines are not fully understood [3]. Liver regeneration is a critical issue related to clinical morbidity and mortality in drug-induced liver injury and after surgery including hepatectomy or living-donor liver transplantation [4, 5]. The temporal development of the signaling pathways specifically activated during liver regeneration may be described in three phases: a priming phase, involving the transition of quiescent hepatocytes from G0 into the G1 phase of the cell cycle; a proliferation phase during which the progression of the entire hepatocyte population occurs; a termination phase during which cell proliferation is suppressed and regeneration is terminated at a defined point [6, 7]. Hepatocytes are not terminally differentiated; rather, the cells are in proliferative quiescence (the G0 phase) but can rapidly enter a cell division cycle upon stimulation [6]. The cytokines/signaling pathways and proteins that are important during the priming phase of regeneration include tumor necrosis factor alpha (TNFα)/nuclear factor κB (NFκB), interleukin-6 (IL-6)/signal transducer and
Omentum facilitates liver regeneration  [cached]
Ashok K Singh, Nishit Pancholi, Jilpa Patel, Natalia O Litbarg, Krishnamurthy P Gudehithlu, Perianna Sethupathi, Mark Kraus, George Dunea, Jose AL Arruda
World Journal of Gastroenterology , 2009,
Abstract: AIM: To investigate the mechanism of liver regeneration induced by fusing the omentum to a small traumatic injury created in the liver. We studied three groups of rats. In one group the rats were omentectomized; in another group the omentum was left in situ and was not activated, and in the third group the omentum was activated by polydextran particles.METHODS: We pre-activated the omentum by injecting polydextran particles and then made a small wedge wound in the rat liver to allow the omentum to fuse to the wound. We monitored the regeneration of the liver by determining the ratio of liver weight/body weight, by histological evaluation (including immune staining for cytokeratin-19, an oval cell marker), and by testing for developmental gene activation using reverse transcription polymerase chain reaction (RT-PCR).RESULTS: There was no liver regeneration in the omentectomized rats, nor was there significant regeneration when the omentum was not activated, even though in this instance the omentum had fused with the liver. In contrast, the liver in the rats with the activated omentum expanded to a size 50% greater than the original, and there was histologically an interlying tissue between the wounded liver and the activated omentum in which bile ducts, containing cytokeratin-19 positive oval cells, extended from the wound edge. In this interlying tissue, oval cells were abundant and appeared to proliferate to form new liver tissue. In rats pre-treated with drugs that inhibited hepatocyte growth, liver proliferation was ongoing, indicating that regeneration of the liver was the result of oval cell expansion.CONCLUSION: Activated omentum facilitates liver regeneration following injury by a mechanism that depends largely on oval cell proliferation.
Liver regeneration in nonalcoholic fatty liver disease  [cached]
Aldo Lagomarsino
Medwave , 2012,
Abstract: Steatosis is the accumulation of fat in hepatocytes, which may be the result of liver regeneration or pathological processes such as alcoholic and nonalcoholic fatty liver disease. Despite its importance, in both cases the exact mechanism that prevails in fatty liver regeneration is poorly understood. Previous studies have shown that patients with fatty liver express dispar regeneration, possibly due to the accumulation of reactive oxygen species generated by inflammatory processes caused by activation of Kupffer cells. In this article we review several factors that affect liver regeneration, trying to understand the underlying mechanism of dispar regeneration in fatty liver as a consequence of nonalcoholic fatty liver disease.
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