Limits...
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

Hepatic gene expression of lipid metabolizing regulators and enzymes.mRNA levels of genes that (a) promote lipid synthesis or (b) promote fatty acid oxidation were determined by Q-PCR analysis. Relative mRNA abundances are expressed as the fold of control (CON-fed WT mice). Data represent mean ± SEM from 4–6 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

License
getmorefigures.php?uid=PMC4940737&req=5

f6: Hepatic gene expression of lipid metabolizing regulators and enzymes.mRNA levels of genes that (a) promote lipid synthesis or (b) promote fatty acid oxidation were determined by Q-PCR analysis. Relative mRNA abundances are expressed as the fold of control (CON-fed WT mice). Data represent mean ± SEM from 4–6 mice. *P < 0.05, vs. diet-matched WT mice. #P < 0.05, vs. CON-fed mice of the same genotype.

Mentions: Hepatic quantitative real-time PCR analysis revealed that in KO mice fed control chow diet, genes promoting lipid synthesis (Srebp1, Fasn, Scd1, and Fads1) were suppressed (Fig. 6a), while genes promoting fatty acid (FA) oxidation (Pgc-1α and Cpt-1) were induced (Fig. 6b). The combined effect of these changes likely explains the 50% decrease in total hepatic TG content in CON-fed KO mice. When comparing EtOH-fed with CON-fed mice, EtOH feeding did not cause changes in liver mRNA levels of three regulators, namely Srebp1, Pparα and Pgc-1α in either WT or KO mice (Fig. 6). In WT mice, among the genes examined, Fads1 (involved in lipogenesis) was found to be up-regulated by EtOH and Acox1 (catalyzes the first step of peroxisomal FA oxidation) was repressed (Fig. 6). In KO mice, two major lipogenic genes, Fasn and Scd1, were suppressed by EtOH, whereas Acox1 was induced (Fig. 6). Notably, Fasn and Scd1 are target genes of SREBP125, and Cpt-1 and Acox1 are PPARα/PGC-1α regulated genes26. Collectively, the expression profiles of genes involved in lipid metabolism were differentially modulated by EtOH in KO mice (relative to WT 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)

Hepatic gene expression of lipid metabolizing regulators and enzymes.mRNA levels of genes that (a) promote lipid synthesis or (b) promote fatty acid oxidation were determined by Q-PCR analysis. Relative mRNA abundances are expressed as the fold of control (CON-fed WT mice). Data represent mean ± SEM from 4–6 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

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

f6: Hepatic gene expression of lipid metabolizing regulators and enzymes.mRNA levels of genes that (a) promote lipid synthesis or (b) promote fatty acid oxidation were determined by Q-PCR analysis. Relative mRNA abundances are expressed as the fold of control (CON-fed WT mice). Data represent mean ± SEM from 4–6 mice. *P < 0.05, vs. diet-matched WT mice. #P < 0.05, vs. CON-fed mice of the same genotype.
Mentions: Hepatic quantitative real-time PCR analysis revealed that in KO mice fed control chow diet, genes promoting lipid synthesis (Srebp1, Fasn, Scd1, and Fads1) were suppressed (Fig. 6a), while genes promoting fatty acid (FA) oxidation (Pgc-1α and Cpt-1) were induced (Fig. 6b). The combined effect of these changes likely explains the 50% decrease in total hepatic TG content in CON-fed KO mice. When comparing EtOH-fed with CON-fed mice, EtOH feeding did not cause changes in liver mRNA levels of three regulators, namely Srebp1, Pparα and Pgc-1α in either WT or KO mice (Fig. 6). In WT mice, among the genes examined, Fads1 (involved in lipogenesis) was found to be up-regulated by EtOH and Acox1 (catalyzes the first step of peroxisomal FA oxidation) was repressed (Fig. 6). In KO mice, two major lipogenic genes, Fasn and Scd1, were suppressed by EtOH, whereas Acox1 was induced (Fig. 6). Notably, Fasn and Scd1 are target genes of SREBP125, and Cpt-1 and Acox1 are PPARα/PGC-1α regulated genes26. Collectively, the expression profiles of genes involved in lipid metabolism were differentially modulated by EtOH in KO mice (relative to WT 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