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Suppression of PGC-1alpha by Ethanol: Implications of Its Role in Alcohol Induced Liver Injury.

ABSTRACT: Ethanol has been known to cause injury to the liver and other tissues; however the molecular factors responsible for alcohol induced liver injury has not been fully understood. Recent studies indicate that reactive oxygen species (ROS) may play an important role in alcohol induced liver injury. Peroxisome proliferator activated receptor-gamma (PPAR-gamma)-coactivator 1alpha (PGC-1alpha) has been shown to be involved in defenses against ROS by inducing many ROS-detoxifying enzymes. However, the role of PGC-1alpha in alcohol induced liver injury has not been elucidated. Therefore, in this study, we examined the effect of alcohol on gene and protein expression of PGC-1alpha in H4-IIE cells (in vitro) and hepatic tissues (in vivo) by real-time PCR and Western blot, respectively. Our results show that exposure to 500 mM ethanol in H4-IIE cells for 24 h significantly decreased both gene and protein expression of PGC-1alpha. PGC-1alpha gene expression was significantly decreased in cells exposed to 100 ng/ml LPS or 1% hypoxia for 24 h. In addition, PGC-1alpha gene and protein expressions were slightly lower in hepatic tissues of rats exposed to ethanol for 15 h, at the level equivalent to the 500 mM used in culture cells, in comparison to sham rats. In contrast, serum LDH and AST levels in ethanol exposed rats were 1.9 fold and 2.8 fold higher than that of sham rats, respectively, which suggest significant organ injury in these rats following ethanol exposure. Likewise, catalase, an enzyme that hydrolyzes peroxide to water, is significantly increased in ethanol exposed H4-IIE cells which further confirms ROS generation due to ethanol exposure. Thus, our results show that oxidative stress conditions such as acute alcohol consumption, LPS or hypoxia suppresses PGC-1alpha expression in the liver, thereby presumably downregulates pertinent ROS-scavenging enzymes and enhances liver injury.

SUBMITTER: Chaung WW

PROVIDER: S-EPMC2596315 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Suppression of PGC-1alpha by Ethanol: Implications of Its Role in Alcohol Induced Liver Injury.

Chaung Wayne W WW Jacob Asha A Ji Youxin Y Wang Ping P

International journal of clinical and experimental medicine 20080321 2

Ethanol has been known to cause injury to the liver and other tissues; however the molecular factors responsible for alcohol induced liver injury has not been fully understood. Recent studies indicate that reactive oxygen species (ROS) may play an important role in alcohol induced liver injury. Peroxisome proliferator activated receptor-gamma (PPAR-gamma)-coactivator 1alpha (PGC-1alpha) has been shown to be involved in defenses against ROS by inducing many ROS-detoxifying enzymes. However, the r ...[more]

PMID: 19079670

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Project description:OBJECTIVE:Excess ethanol consumption has serious pathologic consequences. In humans, repeated episodes of binge drinking can lead to liver damage and have adverse effects on other organs such as pancreas and brain. Long term chronic consumption of ethanol can also result in progressive alcoholic liver disease and cirrhosis. Fibroblast growth factor 21 (FGF21) is a metabolic regulator with multiple physiologic functions. FGF21 is a novel biomarker for non-alcoholic fatty liver disease (NAFLD) in humans and limits hepatotoxicity in mice. Therefore, we explored the possibility that FGF21 plays a role in response to ethanol consumption in both humans and mice. METHODS:We used a binge drinking paradigm in humans to examine the effect of acute ethanol consumption on circulating FGF21. We adapted this paradigm to evaluate the acute response to ethanol in mice. We then examined the role of FGF21 on liver pathology in two models of chronic ethanol consumption in both wild type (WT) mice and mice lacking FGF21 (FGF21-KO). RESULTS:Acute ethanol consumption resulted in a robust induction of serum FGF21 after 6 h in both humans and mice. Serum ethanol peaked at 1 h in both species and was cleared by 6 h. Ethanol clearance was the same in WT and FGF21-KO mice, indicating that FGF21 does not play a major role in ethanol metabolism in a binge paradigm. When FGF21-KO mice were fed the Lieber-DeCarli diet, a high fat diet supplemented with ethanol, a higher mortality was observed compared to WT mice after 16 days on the diet. When FGF21-KO mice consumed 30% ethanol in drinking water, along with a normal chow diet, there was no mortality observed even after 16 weeks, but the FGF21-KO mice had significant liver pathology compared to WT mice. CONCLUSIONS:Acute or binge ethanol consumption significantly increases circulating FGF21 levels in both humans and mice. However, FGF21 does not play a role in acute ethanol clearance. In contrast, chronic ethanol consumption in the absence of FGF21 is associated with significant liver pathology alone or in combination with excess mortality, depending on the type of diet consumed with ethanol. This suggests that FGF21 protects against long term ethanol induced hepatic damage and may attenuate progression of alcoholic liver disease. Further study is required to assess the therapeutic potential of FGF21 in the treatment of alcoholic liver disease.

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Suppression of PGC-1alpha by Ethanol: Implications of Its Role in Alcohol Induced Liver Injury.

Publications

Suppression of PGC-1alpha by Ethanol: Implications of Its Role in Alcohol Induced Liver Injury.

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