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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

Lipidomic analysis of liver cholesterol ester (CE) and triglycerides (TG).Hepatic neutral lipids were profiled by mass spectrometry from liver lipid extracts obtained from WT and KO mice fed regular chow (REG), control (CON) or ethanol (EtOH) liquid diets for 6 wk. Total liver CE (a) and TG (c) content were calculated by summing the amounts of all molecular species present in each lipid class. Relative abundance of each lipid species in the CE (b) and TG (d) class upon EtOH treatment was calculated as the fold change in respective CON-fed groups. Data are mean ± SEM from 4–5 mice. *P < 0.05, vs. diet-matched WT mice.
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f4: Lipidomic analysis of liver cholesterol ester (CE) and triglycerides (TG).Hepatic neutral lipids were profiled by mass spectrometry from liver lipid extracts obtained from WT and KO mice fed regular chow (REG), control (CON) or ethanol (EtOH) liquid diets for 6 wk. Total liver CE (a) and TG (c) content were calculated by summing the amounts of all molecular species present in each lipid class. Relative abundance of each lipid species in the CE (b) and TG (d) class upon EtOH treatment was calculated as the fold change in respective CON-fed groups. Data are mean ± SEM from 4–5 mice. *P < 0.05, vs. diet-matched WT mice.

Mentions: Histological and biochemical examination of the liver demonstrated KO mice to be resistant to EtOH-induced steatosis (Fig. 1 and Table 1). To characterize the nature of changes in lipid composition by genotype and/or by EtOH treatment, hepatic neutral lipids (including cholesterol ester (CE) and triglyceride (TG)) were quantitated and profiled. Both lipid families showed differences in total hepatic content that were genotype-dependent (Fig. 4a,c), as well as changes in specific lipid species that were influenced by EtOH treatment (Fig. 4b,d). Specifically, total hepatic CE content in KO mice was 40% lower than in WT mice fed regular chow diet; such a difference was not observed following liquid diet treatment (Fig. 4a). While EtOH did not affect the total content of CE regardless of the genotype (Fig. 4a), saturated and monounsaturated CE species were maintained at higher levels in the KO liver relative to the WT liver following chronic EtOH consumption (Fig. 4b). On the other hand, EtOH feeding increased hepatic TG concentration by 50% in WT mice; no such increase occurred in KO mice (Fig. 4c). KO mice showed lower levels of hepatic TG in all diet groups (Fig. 4c), an observation that is in agreement with our biochemical analyses (Table 1). Despite having ≈50% lower total TG content than WT mice, KO mice showed a general trend of increases in the degree of unsaturation in triglycerides in response to EtOH feeding (Fig. 4d). This indicated that, along with an overall decrease in TG synthesis, specific pathways/enzymes involved in polyunsaturated fatty acid (PUFA) synthesis may be stimulated in the livers of KO mice.


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)

Lipidomic analysis of liver cholesterol ester (CE) and triglycerides (TG).Hepatic neutral lipids were profiled by mass spectrometry from liver lipid extracts obtained from WT and KO mice fed regular chow (REG), control (CON) or ethanol (EtOH) liquid diets for 6 wk. Total liver CE (a) and TG (c) content were calculated by summing the amounts of all molecular species present in each lipid class. Relative abundance of each lipid species in the CE (b) and TG (d) class upon EtOH treatment was calculated as the fold change in respective CON-fed groups. Data are mean ± SEM from 4–5 mice. *P < 0.05, vs. diet-matched WT mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Lipidomic analysis of liver cholesterol ester (CE) and triglycerides (TG).Hepatic neutral lipids were profiled by mass spectrometry from liver lipid extracts obtained from WT and KO mice fed regular chow (REG), control (CON) or ethanol (EtOH) liquid diets for 6 wk. Total liver CE (a) and TG (c) content were calculated by summing the amounts of all molecular species present in each lipid class. Relative abundance of each lipid species in the CE (b) and TG (d) class upon EtOH treatment was calculated as the fold change in respective CON-fed groups. Data are mean ± SEM from 4–5 mice. *P < 0.05, vs. diet-matched WT mice.
Mentions: Histological and biochemical examination of the liver demonstrated KO mice to be resistant to EtOH-induced steatosis (Fig. 1 and Table 1). To characterize the nature of changes in lipid composition by genotype and/or by EtOH treatment, hepatic neutral lipids (including cholesterol ester (CE) and triglyceride (TG)) were quantitated and profiled. Both lipid families showed differences in total hepatic content that were genotype-dependent (Fig. 4a,c), as well as changes in specific lipid species that were influenced by EtOH treatment (Fig. 4b,d). Specifically, total hepatic CE content in KO mice was 40% lower than in WT mice fed regular chow diet; such a difference was not observed following liquid diet treatment (Fig. 4a). While EtOH did not affect the total content of CE regardless of the genotype (Fig. 4a), saturated and monounsaturated CE species were maintained at higher levels in the KO liver relative to the WT liver following chronic EtOH consumption (Fig. 4b). On the other hand, EtOH feeding increased hepatic TG concentration by 50% in WT mice; no such increase occurred in KO mice (Fig. 4c). KO mice showed lower levels of hepatic TG in all diet groups (Fig. 4c), an observation that is in agreement with our biochemical analyses (Table 1). Despite having ≈50% lower total TG content than WT mice, KO mice showed a general trend of increases in the degree of unsaturation in triglycerides in response to EtOH feeding (Fig. 4d). This indicated that, along with an overall decrease in TG synthesis, specific pathways/enzymes involved in polyunsaturated fatty acid (PUFA) synthesis may be stimulated in the livers of KO mice.

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