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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

Scheme of proposed mechanisms underlying the protective phenotype of KO mice.We propose that chronic GSH depletion induces redox activation of LKB1/AMPK pathway (through phosphorylation of AMPKα subunit) that serves as a central link triggering multiple metabolic and stress response preventing ALD. These downstream pathways include (enhanced) ethanol metabolism, (suppressed) lipid synthesis and (enhanced) fatty acid oxidation, (activated) NRF2 pathway and unidentified pathways (e.g. ER stress and mitochondrial function).
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f7: Scheme of proposed mechanisms underlying the protective phenotype of KO mice.We propose that chronic GSH depletion induces redox activation of LKB1/AMPK pathway (through phosphorylation of AMPKα subunit) that serves as a central link triggering multiple metabolic and stress response preventing ALD. These downstream pathways include (enhanced) ethanol metabolism, (suppressed) lipid synthesis and (enhanced) fatty acid oxidation, (activated) NRF2 pathway and unidentified pathways (e.g. ER stress and mitochondrial function).

Mentions: In conclusion, we show that chronic in vivo GSH deficiency, despite inducing CYP2E1 and hepatic oxidative stress, triggers adaptive mechanisms that protect the liver against ethanol-induced toxicity. Protection is likely mediated by redox activation of the AMPK and NRF2 pathways. It should be noted that recent studies have shown convergence between these two pathways such that AMPK activation is an upstream event of the NRF2-mediated antioxidant response53. Taken together, we propose that chronic GSH depletion induces redox activation of the AMPK pathway that may serve as the central link triggering mechanisms that prevent alcohol-induced liver injury (as illustrated in Fig. 7). This novel pathway may represent a new therapeutic target for preventing ALD and perhaps non-alcoholic liver steatosis.


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)

Scheme of proposed mechanisms underlying the protective phenotype of KO mice.We propose that chronic GSH depletion induces redox activation of LKB1/AMPK pathway (through phosphorylation of AMPKα subunit) that serves as a central link triggering multiple metabolic and stress response preventing ALD. These downstream pathways include (enhanced) ethanol metabolism, (suppressed) lipid synthesis and (enhanced) fatty acid oxidation, (activated) NRF2 pathway and unidentified pathways (e.g. ER stress and mitochondrial function).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: Scheme of proposed mechanisms underlying the protective phenotype of KO mice.We propose that chronic GSH depletion induces redox activation of LKB1/AMPK pathway (through phosphorylation of AMPKα subunit) that serves as a central link triggering multiple metabolic and stress response preventing ALD. These downstream pathways include (enhanced) ethanol metabolism, (suppressed) lipid synthesis and (enhanced) fatty acid oxidation, (activated) NRF2 pathway and unidentified pathways (e.g. ER stress and mitochondrial function).
Mentions: In conclusion, we show that chronic in vivo GSH deficiency, despite inducing CYP2E1 and hepatic oxidative stress, triggers adaptive mechanisms that protect the liver against ethanol-induced toxicity. Protection is likely mediated by redox activation of the AMPK and NRF2 pathways. It should be noted that recent studies have shown convergence between these two pathways such that AMPK activation is an upstream event of the NRF2-mediated antioxidant response53. Taken together, we propose that chronic GSH depletion induces redox activation of the AMPK pathway that may serve as the central link triggering mechanisms that prevent alcohol-induced liver injury (as illustrated in Fig. 7). This novel pathway may represent a new therapeutic target for preventing ALD and perhaps non-alcoholic liver steatosis.

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