Suppression of PGC-1alpha by Ethanol: Implications of Its Role in Alcohol Induced Liver Injury.
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.
Chaung
Wayne W
WW
Department of Surgery, North Shore University Hospital and Long Island Jewish Medical Center and The Feinstein Institute for Medical Research Manhasset, NY 11030, USA.
Jacob
Asha
A
Ji
Youxin
Y
Wang
Ping
P