The Hepatoprotective Effect of Hepatic Stimulator Substance (HSS) Against Liver Regeneration Arrest Induced by Acute Ethanol Intoxication

Kondili, Vasiliki G.; Tzirogiannis, Konstantinos; Androutsos, Christos D.; Papadimas, George K.; Demonakou, Maria; Hereti, Rosa I.; Manta, Georgia A.; Kourentzi, Kalliopi T.; Triantaphyllou, Maro I.; Panoutsopoulos, Georgios I.

doi:10.1007/s10620-005-1598-9

Cited by 9 publications

(8 citation statements)

References 44 publications

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“…Indeed, ALR has been shown to function as a survival factor for hepatocytes and depletion of ALR protein by antisense oligonucleotide leads to hepatocyte cell death [29]. Acute liver damage induced by toxins, such as ethanol, is known to stimulate hepatic stimulatory substance (HSS) activity in the injured livers, and exogenous HSS administration increased the injured liver hepatic proliferation post toxin treatment [30], [31]. ALR is a purified protein of HSS [1] and has been reported to stimulate hepatocyte proliferation directly as well as indirectly through Kupffer cells [3], [32].…”

Section: Resultsmentioning

confidence: 99%

Augmenter of Liver Regeneration (alr) Promotes Liver Outgrowth during Zebrafish Hepatogenesis

Farooq

Sheng

et al. 2012

PLoS ONE

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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, alr C131S 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.

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Section: Resultsmentioning

confidence: 99%

Augmenter of Liver Regeneration (alr) Promotes Liver Outgrowth during Zebrafish Hepatogenesis

Farooq

Sheng

et al. 2012

PLoS ONE

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“…Previous studies have shown that acute ethanol exposure will impair hepatic regeneration if administered 1 h before or 1 h after PHx surgery in rodents (19,44). However, such a protocol is complicated by the direct and indirect effects of ethanol and/or its metabolites.…”

Section: Discussionmentioning

confidence: 99%

Acute ethanol preexposure promotes liver regeneration after partial hepatectomy in mice by activating ALDH2

Ding

Beier

Baldauf

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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It is known that chronic ethanol significantly impairs liver regeneration. However, the effect of acute ethanol exposure on liver regeneration remains largely unknown. To address this question, C57Bl6/J mice were exposed to acute ethanol (6 g/kg intragastrically) for 3 days, and partial hepatectomy (PHx) was performed 24 h after the last dose. Surprisingly, acute ethanol preexposure promoted liver regeneration. This effect of ethanol did not correlate with changes in expression of cell cycle regulatory genes (e.g., cyclin D1, p21, and p27) but did correlate with protection against the effect of PHx on indices of impaired lipid and carbohydrate metabolism. Ethanol preexposure protected against inhibition of the oxidant-sensitive mitochondrial enzyme, aconitase. The activity of aldehyde dehydrogenase 2 (ALDH2) was significantly increased by ethanol preexposure. The effect of ethanol was blocked by inhibiting (Daidzin) and was mimicked by activating (Alda-1) ALDH2. Lipid peroxides are also substrates for ALDH2; indeed, alcohol preexposure blunted the increase in lipid peroxidation (4OH-nonenal adducts) caused by PHx. Taken together, these data suggest that acute preoperative ethanol exposure "preconditions" the liver to respond more rapidly to regenerate after PHx by activating mitochondrial ALDH2, which prevents oxidative stress in this compartment. aldehyde dehydrogenase 2; alcohol; liver regeneration; oxidative stress THE LIVER HAS TREMENDOUS REGENERATIVE capacity that distinguishes it from other vital organs (e.g., the brain, heart, and lungs) that are far less able to replace functional tissue. As the main detoxifying organ in the body, the liver is prone to toxic injury. Due to its regenerative properties, however, the liver is able to restore to full size and ensure survival. In experimental models (e.g., mice), full regeneration occurs within 7-10 days (36). Although hepatocytes rarely proliferate in the healthy adult liver, virtually all surviving hepatocytes replicate at least once after 70% partial hepatectomy (PHx).In addition to hepatocyte proliferation, there is a tightly coordinated response to complement the regenerative process (34). Perturbations of this complex and synchronized response can impact normal tissue recovery from injury or damage. Indeed, it is now clear that impaired regeneration and/or restitution is critical to the chronicity of numerous hepatic diseases. Studies have shown that chronic ethanol (EtOH) exposure delays the induction of hepatocyte DNA synthesis in response to PHx (20). This effect of chronic ethanol may contribute to impaired regeneration and restitution from damage associated with alcoholic liver disease.In contrast to chronic exposure, little is known about the effect of acute ethanol administration on liver regeneration. Under some conditions, acute and chronic ethanol exposure mediate similar responses in the organ. For example, both acute and chronic ethanol exposure enhance lipopolysaccharide-induced liver damage (1, 6). Should acute ethanol exposure also impair...

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“…Inhibition of microtubule formation has significant implications for mitosis, as well as intracellular trafficking, likely contributing to mitotic arrest at the metaphase/anaphase transition, formation of the mitochondrial permeability transition pore, and the subsequent initiation of apoptotic signaling involving the upregulation of pro-apoptotic Bcl-2 family proteins such as Bax/Bad/Bim and subsequent caspase activation (Bhalla, 2003; Giacca, 2005). This is likely a critical aspect of both hepatic injury associated with chronic ethanol exposure (e.g., Kondili et al, 2005) and ethanol-associated abnormalities in fetal brain and craniofacial development (e.g. Sulik et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

Ethanol impairs microtubule formation via interactions at a microtubule associated protein-sensitive site

Smith

Butler

Prendergast

2013

Alcohol

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Prolonged ethanol abuse has been associated with brain injury caused by impaired synaptogenesis, cellular migration, neurogenesis, and cell signaling, all of which require proper microtubule functioning. However, the means by which ethanol may impair microtubule formation or function and the role that microtubule-associated proteins (MAPs) have in mediating such effects are not clear. In the present studies, purified MAP-deficient (2 mg/mL) and MAP-rich (pre-conjugated; 1 mg/mL) bovine α/β tubulin dimer were allowed to polymerize at 37 °C, forming microtubules in the presence or absence of ethanol (25–500 mM). Microtubule formation was assessed in a 96-well format using a turbidity assay, with absorption measured at 340 nm for 45 min. Additional studies co-exposed α/β tubulin dimers to 50 mM ethanol and purified MAPs (0.1 mg/mL) for 45 min. Polymerization of MAP-deficient tubulin was significantly decreased (at 15–45 min of polymerization) during exposure to ethanol (> 25 mM). In contrast, ethanol exposure did not alter polymerization of α/β tubulin dimers pre-conjugated to MAPs, at any concentration. Concurrent exposure of MAP-deficient tubulin with purified MAPs and ethanol resulted in significant and time-dependent decreases in tubulin polymerization, with recovery from inhibition at later time points. The present results suggest that ethanol disrupts MAP-independent microtubule formation and MAP-dependent microtubule formation via direct actions at a MAP-sensitive microtubule residue, indicating that disruption of neuronal microtubule formation and function may contribute to the neurodegenerative effects of binge-like ethanol intake.

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The Hepatoprotective Effect of Hepatic Stimulator Substance (HSS) Against Liver Regeneration Arrest Induced by Acute Ethanol Intoxication

Cited by 9 publications

References 44 publications

Augmenter of Liver Regeneration (alr) Promotes Liver Outgrowth during Zebrafish Hepatogenesis

Augmenter of Liver Regeneration (alr) Promotes Liver Outgrowth during Zebrafish Hepatogenesis

Acute ethanol preexposure promotes liver regeneration after partial hepatectomy in mice by activating ALDH2

Ethanol impairs microtubule formation via interactions at a microtubule associated protein-sensitive site

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