Ethanol Treatment Up Regulates the Expression of Mitochondrial Manganese Superoxide Dismutase in Rat Liver

Koch, Osvaldo R.; DeLeo, M.; Borrello, Silvia; Palombini, G.; Galeotti, T.

doi:10.1006/bbrc.1994.1853

Cited by 75 publications

(45 citation statements)

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“…Another study has shown that Mn-SOD levels were higher in alcohol-mediated liver injury as compared to nonalcoholic liver injury, suggesting the potential of alcohol to generate a higher level of OS [36]. Thus, higher SOD levels among ALD patients may represent direct induction of SOD by alcohol [37]. Earlier studies on SOD levels among NAFLD patients have reported conflicting results [38,39].…”

Section: Discussionmentioning

confidence: 99%

Comparative redox status in alcoholic liver disease and nonalcoholic fatty liver disease

et al. 2008

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Purpose Altered redox status has been implicated in pathogenesis of alcoholic liver disease (ALD) as well as in nonalcoholic fatty liver disease (NAFLD). This study was planned to find the relative role of redox status in these two diseases. Methods A total of 44 patients with ALD and 32 patients with NAFLD and 25 apparently healthy controls were included in the study. Redox status was estimated by measuring oxidative stress (superoxide dismutase (SOD) and lipid peroxidation products as thiobarbituric acid reactive substances (TBARS)) and antioxidant status (ferric reducing ability of plasma (FRAP) and vitamin C). Results TBARS level was raised significantly in both ALD (3.5 (2.3-9.4) vs. 1.8 (0.5-4.1) nmol/ml; P = 0.0001) and NAFLD (5.1 (1-10.2) vs. 1.82 (0.51-4.1) nmol/ml; P = 0.0001) as compared with controls, but was not different between ALD and NAFLD. SOD was significantly higher in ALD as compared to NAFLD (2.4 (1.3-7.8) vs. 0.68 (0.05-19.1) U/ml; P = 0.0001) and controls (1.12 (0.01-3.5) U/ml; P = 0.001). FRAP was lower in ALD as compared with 3) lmol of Fe +2 liberated; P = 0.001) but similar to that of controls (340.9 (141.5-697.5) lmol of Fe +2 liberated). Conclusions ALD patients have a higher degree of redox imbalance as compared with NAFLD patients

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Section: Discussionmentioning

confidence: 99%

Comparative redox status in alcoholic liver disease and nonalcoholic fatty liver disease

et al. 2008

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“…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.…”

mentioning

confidence: 88%

“…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. Decreased food intake compensated for caloric intake from ethanol-sucrose, as confirmed by the fact that weight gain curves between treated and control mice were superimposable (not shown).…”

Section: Ethanol Intoxicationmentioning

confidence: 99%

“…34,29 According to the latter model, SOD2 is expected to be hyper-expressed in p66-deficient tissues; importantly, several lines of evidence indicate a protective role for MnSOD in ethanol-related liver pathology. 11,13,14,16 In search for a mechanism linking lack of p66shc and increased hepatocyte resistance to alcohol injury, we assessed the expression level of SOD2 in the liver of p66À/À and p66 þ / þ mice. As indicated by the western blot analysis shown in Figure 3c, mice from the two control groups (p66 þ / þ ctrl and p66À/À ctrl) expressed comparable amounts of immunoreactive SOD2; however, exposure to ethanol increased SOD2 expression in mutant mice, whereas enzyme upregulation was nearly absent in p66 þ / þ animals.…”

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

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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“…Indeed, cirrhotics possessing two copies of the low-activity, valine-SOD2 variant and high-activity, proline-GPx1 variant are protected from cancer. Furthermore, chronic alcohol consumption is known to increase SOD2 activity [130,131] and decrease mitochondria GPx1 activity [81]. Thus, an imbalance resulting in increased hydrogen peroxide formation and decreased detoxification may be a critical event for the initiation and progression of alcohol induced liver injury.…”

Section: Genetic Factors Determining the Pathobiology Of Fatty Liver mentioning

confidence: 99%

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mantena

King

Andringa

et al. 2008

Free Radical Biology and Medicine

383

302

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Fatty liver disease associated with chronic alcohol consumption or obesity/type 2 diabetes has emerged as a serious public health problem. Steatosis, accumulation of triglyceride in hepatocytes, is now recognized as a critical "first-hit" in the pathogenesis of liver disease. It is proposed that steatosis "primes" the liver to progress to more severe liver pathologies when individuals are exposed to subsequent metabolic and/or environmental stressors or "second-hits". Genetic risk factors can also influence the susceptibility and severity of fatty liver disease. Furthermore, oxidative stress, disrupted nitric oxide (NO) signaling, and mitochondrial dysfunctional are proposed to be key molecular events that accelerate or worsen steatosis and initiate progression to steatohepatitis and fibrosis. This review article will discuss the following topics regarding the pathobiology and molecular mechanisms responsible for fatty liver disease: 1) the "two-hit" or "multi-hit" hypothesis; 2) the role of mitochondrial bioenergetic defects and oxidant stress; 3) interplay between NO and mitochondria in fatty liver disease; 4) genetic risk factors and oxidative stress responsive genes; and 5) the feasibility of antioxidants for treatment.

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Ethanol Treatment Up Regulates the Expression of Mitochondrial Manganese Superoxide Dismutase in Rat Liver

Cited by 75 publications

References 0 publications

Comparative redox status in alcoholic liver disease and nonalcoholic fatty liver disease

Comparative redox status in alcoholic liver disease and nonalcoholic fatty liver disease

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

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

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