Abrogation of hepatocyte apoptosis and early appearance of liver dysplasia in ethanol-fed p53-deficient mice

Pani, Giovambattista; Fusco, Salvatore; Colavitti, Renata; Borrello, Silvia; Maggiano, Nicola; Cravero, Amerys; Farré, Stella M.; Galeotti, T.; Koch, Osvaldo R.

doi:10.1016/j.bbrc.2004.09.213

Cited by 43 publications

(41 citation statements)

References 13 publications

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“…16 Food and water/ethanol consumption, and weight gain curves did not present significant differences between the two mouse strains (not shown), ensuring that mutant and normal mice were exposed to comparable amounts of alcohol and to a similar dietary regimen.…”

Section: Attenuated Liver Damage By Alcohol In P66à/à Micementioning

confidence: 87%

“…11,16 Mice were monitored daily for clinical appearance, weight gain and drinking rate (about 5 ml per mouse per day with no differences among the four groups). As treatment consistently decreased food intake in both WT and p66À/À groups, diet in the ethanol groups was substantially enriched in vitamins and micronutrients, as previously described, 11 to minimize the confounding effect of potential malnutrition on liver parameters.…”

Section: Ethanol Intoxicationmentioning

confidence: 99%

“…10 In keeping with this general scheme, manganese-dependent mitochondrial superoxide dismutase is upregulated by ethanol treatment in rat liver, 11 and modulation of antioxidant enzymes superoxide dismutases 1 (cytosolic) and 2 (mitochondrial) and catalase have been shown to affect alcohol hepatotoxicity both in vivo 12,13 and in vitro. 14,15 Moreover, we have recently reported that, in ethanol-fed mice, hepatocyte apoptosis is largely mediated by the tumor suppressor protein p53, 16 which promotes cell death through the mitochondrial generation of oxidant intermediates. 17 Importantly, resistance to liver apoptosis in p53-deficient mice correlates with elevated expression of the mitochondrial superoxide dismutase.…”

mentioning

confidence: 99%

“…17 Importantly, resistance to liver apoptosis in p53-deficient mice correlates with elevated expression of the mitochondrial superoxide dismutase. 16 In recent years, much attention has been drawn by the signaling adapter protein p66shcA, as a major determinant of cell resistance to oxidative stress and to oxidant-induced cell damage and death. 18 This molecule is in part localized in mitochondria where it promotes, through mechanisms only partially clarified, 19 the generation of ROS in response to an array of noxious stimuli.…”

mentioning

confidence: 99%

“…20 Reproduction of the pathological effects of chronic ethanol abuse in alcohol-fed rodents, along with the increasing availability of genetically modified mouse strains has, in the last few years, significantly contributed to understanding of the molecular basis of ethanol toxicity. 12,16,[24][25][26][27] Prompted by the recent emphasis on the role of p66shc in oxidant-induced cell damage and aging, and in view of the recognized role of mitochondrial oxidative stress in tissue injury by alcohol, we sought to evaluate the pathological effects of ethanol feeding in mice deficient of p66shc, in comparison to p66-proficient littermates. In parallel, we investigated in vitro the response of primary hepatocytes from wild-type and p66À/À mice, and of an ethanol-metabolizing human hepatocellular carcinoma, to physiologically relevant amounts of ethanol.…”

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confidence: 99%

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Role of the life span determinant P66shcA in ethanol-induced liver damage

Koch

Fusco²,

Ranieri³

et al. 2008

Laboratory Investigation

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Mice lacking the 66 kDa isoform of the adapter molecule shcA (p66 shcA ) display increased resistance to oxidative stress and delayed aging. In cultured cell lines, p66 promotes formation of Reactive Oxygen Species (ROS) in mitochondria, and apoptotic cell death in response to a variety of pro-oxidant noxious stimuli. As mitochondrial ROS and oxidative cell damage are clearly involved in alcohol-induced pathology, we hypothesized that p66 may also have a role in ethanol. In vivo, changes observed in p66 þ / þ mice after 6-week exposure to ethanol in the drinking water, including elevated serum alanine aminotransferase (ALT), liver swelling and evident liver steatosis, were significantly attenuated in p66À/À mutant mice. Biochemical analysis of liver tissues revealed induction of the p66 protein by ethanol, whereas p66-deficient livers responded to alcohol with a significant upregulation of the mitochondrial antioxidant enzyme MnSOD, nearly absent in control mice. Evidence of an inverse correlation between expression level of p66 and protection from alcohol-induced oxidative stress was also confirmed in vitro in primary hepatocytes and in HepG2-E47 cells, an ethanol-responsive hepatoma cell line. In fact, MnSOD upregulation by exposure to ethanol in vitro was much more pronounced in p66KO versus wild-type isolated liver cells, and blunted in HepG2 cells overexpressing p66shc. p66 overexpression also prevented the activation of a luciferase reporter gene controlled by the SOD2 promoter, indicating that p66 repression of MnSOD operates at a transcriptional level. Finally, p66 generated ROS in HepG2 cells and potentiated oxidative stress and mitochondrial depolarization by ethanol. Taken together, the above observations clearly indicate a role for p66 in alcohol-induced cell damage, likely via a cell-autonomous mechanism involving reduced expression of antioxidant defenses and mitochondrial dysfunction.

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Section: Attenuated Liver Damage By Alcohol In P66à/à Micementioning

confidence: 87%

Section: Ethanol Intoxicationmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Role of the life span determinant P66shcA in ethanol-induced liver damage

Koch

Fusco²,

Ranieri³

et al. 2008

Laboratory Investigation

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Alcohol‐mediated calcium signals dysregulate pro‐survival Snai2/PUMA/Bcl2 networks to promote p53‐mediated apoptosis in avian neural crest progenitors

Flentke

Baulch

Berres

et al. 2019

Birth Defects Research

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Background: Prenatal alcohol exposure causes distinctive craniofacial anomalies that arise, in part, from the apoptotic elimination of neural crest (NC) progenitors that form the face. This vulnerability of NC to alcohol is puzzling as they normally express the transcriptional repressor Snail1/2 (in chick Snai2), which suppresses apoptosis and promotes their migration. Here, we investigate alcohol's impact upon Snai2 function. Methods: Chick cranial NC cells were treated with acute alcohol (52 mM, 2 hr). We evaluated NC migration, gene expression, proliferation, and apoptosis thereafter. Results: Transient alcohol exposure induced Snai2 (191% ± 23%; p = .003) and stimulated NC migration (p = .0092). An alcohol-induced calcium transient mediated this Snai2 induction, and BAPTA-AM blocked whereas ionomycin mimicked these pro-migratory effects. Alcohol suppressed CyclinD1 protein content (59.1 ± 12%, p = .007) and NC proliferation (19.7 ± 5.8%, p < .001), but these Snai2-enriched cells still apoptosed in response to alcohol. This was explained because alcohol induced p53 (198 ± 29%, p = .023), and the p53 antagonist pifithrin-α prevented their apoptosis. Moreover, alcohol counteracted Snai2's pro-survival signals, and Bcl2 was repressed (68.5 ± 6.0% of controls, p = .016) and PUMA was not induced, while ATM (1.32-fold, p = .01) and PTEN (1.30-fold, p = .028) were elevated. Conclusions: Alcohol's calcium transient uncouples the Snai2/p53 regulatory loop that normally prevents apoptosis during EMT. This represents a novel pathway in alcohol's neurotoxicity, and complements demonstrations that alcohol suppresses PUMA in mouse NC. We propose that the NCs migratory behavior, and their requirement for Snai2/p53 co-expression, makes them vulnerable to stressors that dysregulate Snai2/p53 interactions, such as alcohol. K E Y W O R D Sapoptosis, cell migration, fetal alcohol spectrum disorder, neural crest, p53, Snai2

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Interleukin-6 is an important mediator for mitochondrial DNA repair after alcoholic liver injury in mice

et al. 2010

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We investigated the hypothesis that a prominent effect of chronic ethanol consumption is mitochondrial DNA (mtDNA) injury and compared this injury in IL-6 knockout (KO) and wild-type (WT) mice. Ethanol feeding for 4 weeks resulted in steatosis and oxidative mtDNA damage (8-OHdG) in both IL-6KO and WT mice. However, the WT mice were able to repair the injury by increased production of mtDNA repair enzymes (OGG-1, Neil 1) and check point (p21, p53) proteins and avoid the mtDNA mutations. By contrast the IL-6 KO mice were unable to repair mtDNA resulting in deletions and diminished transcription of the mtDNA encoded protein cytochrome c oxidase subunit-I (COI). The mitochondrial injury was reflected by decreased membrane potential, reduced levels of ATP, and apoptosis-inducing factor (AIF)-induced apoptosis. Conclusion: IL-6 plays a critical role in allowing the liver to recover from significant mtDNA oxidation caused by alcohol. The data suggests that IL-6 activates mtDNA repair enzymes and induces cell cycle arrest allowing time for mtDNA repair. (HEPATOLOGY 2010;52:2137-2147

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Abrogation of hepatocyte apoptosis and early appearance of liver dysplasia in ethanol-fed p53-deficient mice

Cited by 43 publications

References 13 publications

Role of the life span determinant P66shcA in ethanol-induced liver damage

Role of the life span determinant P66shcA in ethanol-induced liver damage

Alcohol‐mediated calcium signals dysregulate pro‐survival Snai2/PUMA/Bcl2 networks to promote p53‐mediated apoptosis in avian neural crest progenitors

Interleukin-6 is an important mediator for mitochondrial DNA repair after alcoholic liver injury in mice

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