Expression of <i>augmenter of liver regeneration</i> (ALR) in human liver cirrhosis and carcinoma

Thasler, WE; Schlott, Thilo; Thelen, Paul; Hellerbrand, Claus; Bataille, Frauke; Lichtenauer, M.; Schlitt, HJ; Kw, Jauch; Weiss, Thomas S.

doi:10.1111/j.1365-2559.2005.02172.x

Cited by 61 publications

(52 citation statements)

References 54 publications

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“…Liver samples were nontumorous tissues with signs of cirrhosis, fibrosis and inflammation. Furthermore, we performed immunohistochemical analysis of hepatocellular carcinoma (HCC) samples and nontumorous liver samples adjacent to HCC and found ALR expression solely in hepatocytes and cholangiocytes as described earlier ( Figure 5C) (48). ALR immunoreactivity was analyzed using an intensity score and revealed enhanced ALR protein expression in nontumorous liver tissue from patients with HBV infection compared with liver tissue from patients without HBV infection or alcohol intoxication ( Figures 5B, C).…”

Section: Alr Expression Is Enhanced In Hbv-positive Cellssupporting

confidence: 58%

Nrf2 Activates Augmenter of Liver Regeneration (ALR) via Antioxidant Response Element and Links Oxidative Stress to Liver Regeneration

Dayoub

Vogel

Schuett

et al. 2013

Mol Med

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Liver regeneration can be impaired by permanent oxidative stress and activation of nuclear factor erythroid 2-related factor 2 (Nrf2), known to regulate the cellular antioxidant response, and has been shown to improve the process of liver regeneration. A variety of factors regulate hepatic tissue regeneration, among them augmenter of liver regeneration (ALR), attained great attention as being survival factors for the liver with proproliferative and antiapoptotic properties. Here we determined the Nrf2/ antioxidant response element (ARE) regulated expression of ALR and show ALR as a target gene of Nrf2 in vitro and in vivo. The ALR promoter comprises an ARE binding site and, therefore, ALR expression can be induced by ARE-activator tertiary butylhydroquinone (tBHQ) in hepatoma cells and primary human hepatocytes (PHH). Promoter activity and expression of ALR were enhanced after cotransfection of Nrf2 compared with control and dominant negative mutant of Nrf2. Performing partial hepatectomy in livers from Nrf2+/+ mice compared with Nrf2−/− knock-out (KO) mice, we found increased expression of ALR in addition to known antioxidant ARE-regulated genes. Furthermore, we observed increased ALR expression in hepatitis B virus (HBV) compared with hepatitis C virus (HCV) positive hepatoma cells and PHH. Recently, it was demonstrated that HBV infection activates Nrf2 and, now, we add results showing increased ALR expression in liver samples from patients infected with HBV. ALR is regulated by Nrf2, acts as a liver regeneration and antioxidative protein and, therefore, links oxidative stress to hepatic regeneration to ensure survival of damaged cells.

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Section: Alr Expression Is Enhanced In Hbv-positive Cellssupporting

confidence: 58%

Nrf2 Activates Augmenter of Liver Regeneration (ALR) via Antioxidant Response Element and Links Oxidative Stress to Liver Regeneration

Dayoub

Vogel

Schuett

et al. 2013

Mol Med

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“…In practice, administration of an HSS-bearing plasmid by hydrodynamic tail vein injection protects mice from hepatic failure, implying its potential role in clinical application. It has been demonstrated that alterations in HSS gene expression could be observed in relation to pathological states, such as acute liver failure (Li et al, 2011), liver cirrhosis (Gribilas et al, 2009), and hepatocellular carcinoma (Thasler et al, 2005;Dayoub et al, 2011). HSS seems to have additional clinical implications because exogenous HSS administration to rats with thioacetamide-induced liver fibrosis/cirrhosis is able to significantly decrease fibrosis and suppress the onset of cirrhosis (Gribilas et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Adenoviral Gene Transfer of Hepatic Stimulator Substance Confers Resistance Against Hepatic Ischemia–Reperfusion Injury by Improving Mitochondrial Function

Jiang

2013

Human Gene Therapy

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Hepatic stimulator substance (HSS) has been suggested to protect liver cells from various toxins. However, the precise role of HSS in hepatic ischemia-reperfusion (I/R) injury remains unknown. This study aims to elucidate whether overexpression of HSS could attenuate hepatic ischemia-reperfusion injury and its possible mechanisms. Both in vivo hepatic I/R injury in mice and in vitro hypoxia-reoxygenation (H/R) in a cell model were used to evaluate the effect of HSS protection after adenoviral gene transfer. Moreover, a possible mitochondrial mechanism of HSS protection was investigated. Efficient transfer of the HSS gene into liver inhibited hepatic I/R injury in mice, as evidenced by improvement in liver function tests, the preservation of hepatic morphology, and a reduction in hepatocyte apoptosis. HSS overexpression also inhibited H/R-induced cell death, as detected by cell viability and cell apoptosis assays. The underlying mechanism of this hepatic protection might involve the attenuation of mitochondrial dysfunction and mitochondrial-dependent cell apoptosis, as shown by the good preservation of mitochondrial ultrastructure, mitochondrial membrane potential, and the inhibition of cytochrome c leakage and caspase activity. Moreover, the suppression of H/R-induced mitochondrial ROS production and the maintenance of mitochondrial respiratory chain complex activities may participate in this mechanism. This new function of HSS expands the possibility of its application for the prevention of I/R injury, such as hepatic resection and liver transplantation in clinical practice.

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“…Full-text review eliminated one article that was an editorial and did not contain original data. Ultimately, 12 articles were included in the present review (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Study characteristics are summarized in Table I.…”

Section: Resultsmentioning

confidence: 99%

“…The majority of studies suggest ALR mRNA and protein levels to be higher in HCC tissue relative to normal tissue. In HCC tissue, ALR typically demonstrates cytoplasmic localization with a granular quality on immunostaining (20). Dayoub and colleagues, however, observe the short ALR isoform of 15 kDa to be expressed at lower levels in HCC overall, compared to normal liver tissue (11).…”

Section: Hepatocellular Carcinomamentioning

confidence: 99%

“…The majority of included studies observe ALR to be upregulated in malignant cells. In frozen and paraffin-embedded HCC tissue, ALR expression is consistently altered when compared to normal para-tumoral tissue and/or healthy controls (10,11,13,20,21). The majority of studies suggest ALR mRNA and protein levels to be higher in HCC tissue relative to normal tissue.…”

Section: Hepatocellular Carcinomamentioning

confidence: 99%

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Clinical Implications of Augmenter of Liver Regeneration in Cancer: A Systematic Review

Nguyen

Dabir

2017

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Expression of augmenter of liver regeneration (ALR) in human liver cirrhosis and carcinoma

Abstract: The findings suggest an important role for ALR in hepatocellular regeneration in liver cirrhosis as well as in hepatocarcinogenesis and therefore its potential value in the clinical diagnosis of hepatic cirrhosis and cancer.

Cited by 61 publications

References 54 publications

Nrf2 Activates Augmenter of Liver Regeneration (ALR) via Antioxidant Response Element and Links Oxidative Stress to Liver Regeneration

Nrf2 Activates Augmenter of Liver Regeneration (ALR) via Antioxidant Response Element and Links Oxidative Stress to Liver Regeneration

Adenoviral Gene Transfer of Hepatic Stimulator Substance Confers Resistance Against Hepatic Ischemia–Reperfusion Injury by Improving Mitochondrial Function

Clinical Implications of Augmenter of Liver Regeneration in Cancer: A Systematic Review

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