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Chronic Glutathione Depletion Confers Protection against Alcohol-induced Steatosis: Implication for Redox Activation of AMP-activated Protein Kinase Pathway.

Chen Y, Singh S, Matsumoto A, Manna SK, Abdelmegeed MA, Golla S, Murphy RC, Dong H, Song BJ, Gonzalez FJ, Thompson DC, Vasiliou V - Sci Rep (2016)

Bottom Line: The pathogenesis of alcoholic liver disease (ALD) is not well established.However, oxidative stress and associated decreases in levels of glutathione (GSH) are known to play a central role in ALD.We propose redox activation of the AMPK may represent a new therapeutic strategy for preventing ALD.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental Health Sciences, Yale University, New Haven, CT 06520, USA.

ABSTRACT
The pathogenesis of alcoholic liver disease (ALD) is not well established. However, oxidative stress and associated decreases in levels of glutathione (GSH) are known to play a central role in ALD. The present study examines the effect of GSH deficiency on alcohol-induced liver steatosis in Gclm knockout (KO) mice that constitutively have ≈15% normal hepatic levels of GSH. Following chronic (6 week) feeding with an ethanol-containing liquid diet, the Gclm KO mice were unexpectedly found to be protected against steatosis despite showing increased oxidative stress (as reflected in elevated levels of CYP2E1 and protein carbonyls). Gclm KO mice also exhibit constitutive activation of liver AMP-activated protein kinase (AMPK) pathway and nuclear factor-erythroid 2-related factor 2 target genes, and show enhanced ethanol clearance, altered hepatic lipid profiles in favor of increased levels of polyunsaturated fatty acids and concordant changes in expression of genes associated with lipogenesis and fatty acid oxidation. In summary, our data implicate a novel mechanism protecting against liver steatosis via an oxidative stress adaptive response that activates the AMPK pathway. We propose redox activation of the AMPK may represent a new therapeutic strategy for preventing ALD.

No MeSH data available.


Related in: MedlinePlus

Accelerated clearance of ethanol (EtOH) and acetaldehyde (AA) in GCLM KO mice.(a) EtOH and AA pharmacokinetics following acute EtOH administration (5 g/kg, i.p). Inset (upper right): area under the curve (AUC). Data represent mean ± SEM from 4–6 mice. *P < 0.05, vs. WT mice. Concentrations of EtOH and AA in blood (b) and liver (c) from mice fed a control (CON) or EtOH diet for 6 wk. Expression of EtOH- (ADH1, CAT and CYP2E1) and AA- (ALDH2/1A1/1B1) metabolizing enzymes (d), protein levels and enzymatic activity of CYP2E1 (e) and ALDH1A1 (f) in livers from mice fed regular chow (REG), CON or EtOH liquid diets for 6 wk. CYP2E1 activity was expressed as p-nitrophenol (PNP) oxidation activity. Data are mean ± SEM from 4 mice. *P < 0.05, vs. diet-matched WT mice. #P < 0.05, vs. CON-fed mice of the same genotype.
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f2: Accelerated clearance of ethanol (EtOH) and acetaldehyde (AA) in GCLM KO mice.(a) EtOH and AA pharmacokinetics following acute EtOH administration (5 g/kg, i.p). Inset (upper right): area under the curve (AUC). Data represent mean ± SEM from 4–6 mice. *P < 0.05, vs. WT mice. Concentrations of EtOH and AA in blood (b) and liver (c) from mice fed a control (CON) or EtOH diet for 6 wk. Expression of EtOH- (ADH1, CAT and CYP2E1) and AA- (ALDH2/1A1/1B1) metabolizing enzymes (d), protein levels and enzymatic activity of CYP2E1 (e) and ALDH1A1 (f) in livers from mice fed regular chow (REG), CON or EtOH liquid diets for 6 wk. CYP2E1 activity was expressed as p-nitrophenol (PNP) oxidation activity. Data are mean ± SEM from 4 mice. *P < 0.05, vs. diet-matched WT mice. #P < 0.05, vs. CON-fed mice of the same genotype.

Mentions: Pharmacokinetics of blood EtOH and acetaldehyde (AA) in KO mice were compared with those in WT mice (Fig. 2a). Following an acute administration of EtOH (5 g/kg, i.p.), KO animals exhibited 30% and 50% less EtOH and AA accumulation in circulation, respectively, suggesting an increased capacity for liver EtOH and AA metabolism in KO mice. At the end of the 6-wk EtOH feeding, a similar trend was also observed in blood (Fig. 2b) and liver (Fig. 2c). Evaluation of EtOH and AA metabolizing enzymes (Fig. 2d) revealed constitutive induction of CYP2E1 (1.8-fold) and ALDH1A1 (1.4-fold) at both protein and enzymatic activity levels in KO livers relative to WT livers (Fig. 2e,f). However, ethanol feeding induced CYP2E1 expression in WT mice to levels comparable to those observed in KO mice (Fig. 2e).


Chronic Glutathione Depletion Confers Protection against Alcohol-induced Steatosis: Implication for Redox Activation of AMP-activated Protein Kinase Pathway.

Chen Y, Singh S, Matsumoto A, Manna SK, Abdelmegeed MA, Golla S, Murphy RC, Dong H, Song BJ, Gonzalez FJ, Thompson DC, Vasiliou V - Sci Rep (2016)

Accelerated clearance of ethanol (EtOH) and acetaldehyde (AA) in GCLM KO mice.(a) EtOH and AA pharmacokinetics following acute EtOH administration (5 g/kg, i.p). Inset (upper right): area under the curve (AUC). Data represent mean ± SEM from 4–6 mice. *P < 0.05, vs. WT mice. Concentrations of EtOH and AA in blood (b) and liver (c) from mice fed a control (CON) or EtOH diet for 6 wk. Expression of EtOH- (ADH1, CAT and CYP2E1) and AA- (ALDH2/1A1/1B1) metabolizing enzymes (d), protein levels and enzymatic activity of CYP2E1 (e) and ALDH1A1 (f) in livers from mice fed regular chow (REG), CON or EtOH liquid diets for 6 wk. CYP2E1 activity was expressed as p-nitrophenol (PNP) oxidation activity. Data are mean ± SEM from 4 mice. *P < 0.05, vs. diet-matched WT mice. #P < 0.05, vs. CON-fed mice of the same genotype.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4940737&req=5

f2: Accelerated clearance of ethanol (EtOH) and acetaldehyde (AA) in GCLM KO mice.(a) EtOH and AA pharmacokinetics following acute EtOH administration (5 g/kg, i.p). Inset (upper right): area under the curve (AUC). Data represent mean ± SEM from 4–6 mice. *P < 0.05, vs. WT mice. Concentrations of EtOH and AA in blood (b) and liver (c) from mice fed a control (CON) or EtOH diet for 6 wk. Expression of EtOH- (ADH1, CAT and CYP2E1) and AA- (ALDH2/1A1/1B1) metabolizing enzymes (d), protein levels and enzymatic activity of CYP2E1 (e) and ALDH1A1 (f) in livers from mice fed regular chow (REG), CON or EtOH liquid diets for 6 wk. CYP2E1 activity was expressed as p-nitrophenol (PNP) oxidation activity. Data are mean ± SEM from 4 mice. *P < 0.05, vs. diet-matched WT mice. #P < 0.05, vs. CON-fed mice of the same genotype.
Mentions: Pharmacokinetics of blood EtOH and acetaldehyde (AA) in KO mice were compared with those in WT mice (Fig. 2a). Following an acute administration of EtOH (5 g/kg, i.p.), KO animals exhibited 30% and 50% less EtOH and AA accumulation in circulation, respectively, suggesting an increased capacity for liver EtOH and AA metabolism in KO mice. At the end of the 6-wk EtOH feeding, a similar trend was also observed in blood (Fig. 2b) and liver (Fig. 2c). Evaluation of EtOH and AA metabolizing enzymes (Fig. 2d) revealed constitutive induction of CYP2E1 (1.8-fold) and ALDH1A1 (1.4-fold) at both protein and enzymatic activity levels in KO livers relative to WT livers (Fig. 2e,f). However, ethanol feeding induced CYP2E1 expression in WT mice to levels comparable to those observed in KO mice (Fig. 2e).

Bottom Line: The pathogenesis of alcoholic liver disease (ALD) is not well established.However, oxidative stress and associated decreases in levels of glutathione (GSH) are known to play a central role in ALD.We propose redox activation of the AMPK may represent a new therapeutic strategy for preventing ALD.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental Health Sciences, Yale University, New Haven, CT 06520, USA.

ABSTRACT
The pathogenesis of alcoholic liver disease (ALD) is not well established. However, oxidative stress and associated decreases in levels of glutathione (GSH) are known to play a central role in ALD. The present study examines the effect of GSH deficiency on alcohol-induced liver steatosis in Gclm knockout (KO) mice that constitutively have ≈15% normal hepatic levels of GSH. Following chronic (6 week) feeding with an ethanol-containing liquid diet, the Gclm KO mice were unexpectedly found to be protected against steatosis despite showing increased oxidative stress (as reflected in elevated levels of CYP2E1 and protein carbonyls). Gclm KO mice also exhibit constitutive activation of liver AMP-activated protein kinase (AMPK) pathway and nuclear factor-erythroid 2-related factor 2 target genes, and show enhanced ethanol clearance, altered hepatic lipid profiles in favor of increased levels of polyunsaturated fatty acids and concordant changes in expression of genes associated with lipogenesis and fatty acid oxidation. In summary, our data implicate a novel mechanism protecting against liver steatosis via an oxidative stress adaptive response that activates the AMPK pathway. We propose redox activation of the AMPK may represent a new therapeutic strategy for preventing ALD.

No MeSH data available.


Related in: MedlinePlus