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.

内毒素血症与非酒精性脂肪性肝病（NAFLD）之间的联系已在人类和啮齿动物中得到证实。然而，内毒素诱发NAFLD的分子机制仍知之甚少。我们假设活性氧（ROS）介导脂多糖（LPS）诱发的肝脏脂质堆积。褪黑素是一种抗氧化剂。在本研究中，我们研究了褪黑素对LPS诱导的肝脏脂质堆积的影响。我们发现单剂量的LPS显著增加了小鼠肝脏甘油三酯（TG）含量并导致肝脏脂质堆积。进一步分析发现，肝脏固醇调节元件结合蛋白（SREBP）-1c在LPS处理的小鼠中被激活。与肝脏SREBP - 1c激活一致，脂肪酸合酶（FAS）和乙酰辅酶A羧化酶（ACC）这两个SREBP - 1c靶基因在注射LPS的小鼠肝脏中显著上调。褪黑素显著减弱了LPS诱导的SREBP - 1c激活以及SREBP - 1c靶基因的表达。此外，褪黑素降低了血清和肝脏甘油三酯（TG）含量，并阻止了LPS诱导的肝脏脂质堆积。综上所述，这些结果表明ROS可能至少部分介导了LPS诱导的SREBP - 1c激活和肝脏脂质堆积。褪黑素可能作为药物用于预防内毒素诱发的NAFLD。