Abstract
Melatonin is supposed to be an effective hepatoprotective agent. The effects and mechanisms of melatonin on alcoholic fatty liver (AFL) have not been well explored. The aim of this study was to investigate the preventive and therapeutic effects of melatonin on alcohol-induced fatty liver rats. The AFL rats were induced by intragastric infusion of alcohol plus a high-fat diet for 6 weeks, and melatonin (10, 20, 40 mg/kg) was administered by gastric perfusion. We also established fatty acid overload cell model in HepG2 cells to investigate the effect of melatonin on AMP-activated protein kinase (AMPK) activity. The results showed that melatonin (20 and 40 mg/kg) administration significantly reduced alcohol-induced hepatic steatosis with lowering activities of serum alanine aminotransferase, aspartate aminotransferase and levels of serum and hepatic triglyceride. The activity of superoxide dismutase was increased and the content of malondialdehyde was decreased in liver homogenates of rats treated with melatonin. Melatonin increased the phosphorylation of AMPK in the liver tissues of alcohol-induced rats as well. Additionally, in vitro studies showed that melatonin increased the expression of melatonin1A receptor (MT1R), whereas luzindole, a receptor antagonist of melatonin, had no effect on its expression. In addition, melatonin reduced the levels of adenosine 3',5'-cyclic monophosphate (cAMP) and increased the phosphorylation of AMPK, and melatonin treatment could markedly reverse these effects. In conclusion, melatonin could protect against liver injury caused by alcohol gastric perfusion. The effect may be related to alleviating lipid peroxidation and upregulating the activity of AMPK mediated by MT1R signaling pathway.
Highlights
Alcoholic liver disease (ALD) is a main cause of morbidity and mortality all over the world (Gao and Bataller, 2011)
If alcohol abuse continues, hepatic steatosis can progress to the advanced stages of ALD, such as steatohepatitis, fibrosis, cirrhosis and even hepatocellular carcinoma, especially in the presence of co-factors including diabetes (Hassan, 2002), hepatitis virus infection (Gramenzi et al, 2006; Gao and Bataller, 2011) and smoking (Kuper et al, 2000; Marrero et al, 2005)
In the in vitro study, we mainly focused on the contribution of melatonin1A receptor (MT1R) to the reducing lipid accumulation effect of melatonin, looking into its potential capacity to modulate cAMP levels and AMPK activation
Summary
Alcoholic liver disease (ALD) is a main cause of morbidity and mortality all over the world (Gao and Bataller, 2011). If alcohol abuse continues, hepatic steatosis can progress to the advanced stages of ALD, such as steatohepatitis, fibrosis, cirrhosis and even hepatocellular carcinoma, especially in the presence of co-factors including diabetes (Hassan, 2002), hepatitis virus infection (Gramenzi et al, 2006; Gao and Bataller, 2011) and smoking (Kuper et al, 2000; Marrero et al, 2005). Understanding of the mechanisms by which chronic alcohol consumption disrupts lipid metabolism and subsequently accumulates excessive TG in hepatocytes is important and probably provides new insights into the prevention and treatment of ALD. Many mechanisms are supposed to be involved in ALD, including oxidative stress, excess lipid synthesis and inflammation (Kanuri et al, 2009).
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