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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

Resistance to ethanol (EtOH)-induced steatosis in GCLM KO mice.Representative images of liver histology by H&E staining. Squares in upper panels were enlarged in the lower panels. Excessive fat accumulation (steatosis) primarily in the form of macrovesicles (arrows) was only observed in EtOH-fed WT mice. CON, control diet; EtOH, ethanol diet. Magnifications: 100x (upper panels) and 400x (lower panels).
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f1: Resistance to ethanol (EtOH)-induced steatosis in GCLM KO mice.Representative images of liver histology by H&E staining. Squares in upper panels were enlarged in the lower panels. Excessive fat accumulation (steatosis) primarily in the form of macrovesicles (arrows) was only observed in EtOH-fed WT mice. CON, control diet; EtOH, ethanol diet. Magnifications: 100x (upper panels) and 400x (lower panels).

Mentions: Mice were fed a high fat liquid diet containing ethanol (EtOH) or isocaloric control (CON) diet for 6 wk. For EtOH-fed mice, the diet contained 2% v/v EtOH (10.8% total calories) in the first wk and the ethanol content increased weekly by 1% until reaching 5% v/v (27% total calorie). Following the 6-wk feeding period, average daily intake (calories) by WT and KO mice was no different (Table 1). Compared with EtOH-fed WT mice, KO mice were less susceptible to EtOH-induced deleterious effects, including body weight loss (reflected by less body weight gain), liver weight gain and hepatocyte damage (reflected by plasma ALT activity) (Table 1). Most interestingly, the steatosis observed in EtOH-fed WT mice was absent from KO mice (Fig. 1). In line with histological observations, EtOH feeding caused a 50% increase in total hepatic TG content in WT mice, but had no effect on the hepatic TG content in KO mice (Table 1). It is worth noting that histological examination of the liver revealed no significant liver inflammation in either WT or KO mice (Fig. 1), which is further supported by unaltered mRNA levels of inflammatory genes TNFα, IL-6 and IL-1β (supplementary Fig. 1).


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)

Resistance to ethanol (EtOH)-induced steatosis in GCLM KO mice.Representative images of liver histology by H&E staining. Squares in upper panels were enlarged in the lower panels. Excessive fat accumulation (steatosis) primarily in the form of macrovesicles (arrows) was only observed in EtOH-fed WT mice. CON, control diet; EtOH, ethanol diet. Magnifications: 100x (upper panels) and 400x (lower panels).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Resistance to ethanol (EtOH)-induced steatosis in GCLM KO mice.Representative images of liver histology by H&E staining. Squares in upper panels were enlarged in the lower panels. Excessive fat accumulation (steatosis) primarily in the form of macrovesicles (arrows) was only observed in EtOH-fed WT mice. CON, control diet; EtOH, ethanol diet. Magnifications: 100x (upper panels) and 400x (lower panels).
Mentions: Mice were fed a high fat liquid diet containing ethanol (EtOH) or isocaloric control (CON) diet for 6 wk. For EtOH-fed mice, the diet contained 2% v/v EtOH (10.8% total calories) in the first wk and the ethanol content increased weekly by 1% until reaching 5% v/v (27% total calorie). Following the 6-wk feeding period, average daily intake (calories) by WT and KO mice was no different (Table 1). Compared with EtOH-fed WT mice, KO mice were less susceptible to EtOH-induced deleterious effects, including body weight loss (reflected by less body weight gain), liver weight gain and hepatocyte damage (reflected by plasma ALT activity) (Table 1). Most interestingly, the steatosis observed in EtOH-fed WT mice was absent from KO mice (Fig. 1). In line with histological observations, EtOH feeding caused a 50% increase in total hepatic TG content in WT mice, but had no effect on the hepatic TG content in KO mice (Table 1). It is worth noting that histological examination of the liver revealed no significant liver inflammation in either WT or KO mice (Fig. 1), which is further supported by unaltered mRNA levels of inflammatory genes TNFα, IL-6 and IL-1β (supplementary Fig. 1).

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