Melatonin alleviates lipopolysaccharide-induced hepatic SREBP-1c activation and lipid accumulation in mice.

A link between endotoxemia and nonalcoholic fatty liver disease (NAFLD) has been demonstrated in human and rodent animals. Nevertheless, the molecular mechanisms of endotoxin-evoked NAFLD remain poorly understood. We hypothesize that reactive oxygen species (ROS) mediate lipopolysaccharide (LPS)-evoked hepatic lipid accumulation. Melatonin is an antioxidant. In the present study, we investigated the effects of melatonin on LPS-induced hepatic lipid accumulation. We showed that a single dose of LPS significantly increased hepatic triglyceride (TG) contents and caused hepatic lipid accumulation in mice. Further analysis found that hepatic sterol regulatory element-binding protein (SREBP)-1c was activated in LPS-treated mice. In agreement with hepatic SREBP-1c activation, fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), two SREBP-1c target genes, were significantly upregulated in liver of mice injected with LPS. Melatonin significantly attenuated LPS-induced SREBP-1c activation and the expression of SREBP-1c target genes. In addition, melatonin reduced serum and hepatic triglyceride (TG) content and prevented LPS-induced hepatic lipid accumulation. Taken together, these results suggest that ROS might be, at least partially, mediated in LPS-induced SREBP-1c activation and hepatic lipid accumulation. Melatonin may be useful as pharmacological agents to protect against endotoxin-evoked NAFLD.