尽管禁食会在啮齿动物和人类中诱导肝甘油三酯(TG)积累,对潜在的机制知之甚少。因为副交感神经系统活动倾向于减弱极低密度脂蛋白甘油三酯(VLDL-TG)的分泌并增加肝脏中的TG存储,脂肪肝患者血清胆碱酯酶活性升高,副交感神经递质乙酰胆碱酯酶(AChE)的抑制可能对肝脏脂质代谢有一定影响。为了评估AChE抑制对脂质代谢的影响,毒扁豆碱的作用,AChE抑制剂,在小鼠中研究了空腹诱导的肝脏TG升高。与随意喂食的小鼠相比,30小时空腹增加肝脏TG积累,同时下调固醇调节元件结合蛋白1(SREBP-1)和肝脏脂肪酸结合蛋白(L-FABP)。毒扁豆碱以剂量依赖性方式促进30h禁食诱导的肝脏TG水平升高,伴随着血浆胰岛素水平的显著下降,血浆TG没有下降。此外,毒扁豆碱显着减弱了空腹诱导的SREBP-1和L-FABPmRNA和蛋白质水平的降低,肝脏中IRS-2蛋白水平升高。毒蕈碱受体拮抗剂阿托品阻断毒扁豆碱对肝脏TG的这些作用,血清胰岛素,和SREBP-1和L-FABP的肝蛋白水平。这些结果表明,AChE抑制促进小鼠空腹诱导的TG积累,并上调肝脏L-FABP和SREBP-1,至少部分通过激活毒蕈碱乙酰胆碱受体。我们的研究强调了副交感神经调节在空腹诱导的TG积累中的关键作用,可能是肝脏脂质代谢紊乱机制的重要信息来源。
Although fasting induces hepatic triglyceride (TG) accumulation in both rodents and humans, little is known about the underlying mechanism. Because parasympathetic nervous system activity tends to attenuate the secretion of very-low-density-lipoprotein-triglyceride (VLDL-TG) and increase TG stores in the liver, and serum cholinesterase activity is elevated in fatty liver disease, the inhibition of the parasympathetic neurotransmitter acetylcholinesterase (AChE) may have some influence on hepatic lipid metabolism. To assess the influence of AChE inhibition on lipid metabolism, the effect of physostigmine, an AChE inhibitor, on fasting-induced increase in liver TG was investigated in mice. In comparison with ad libitum-fed mice, 30 h fasting increased liver TG accumulation accompanied by a downregulation of sterol regulatory element-binding protein 1 (SREBP-1) and liver-fatty acid binding-protein (L-FABP). Physostigmine promoted the 30 h fasting-induced increase in liver TG levels in a dose-dependent manner, accompanied by a significant fall in plasma insulin levels, without a fall in plasma TG. Furthermore, physostigmine significantly attenuated the fasting-induced decrease of both mRNA and protein levels of SREBP-1 and L-FABP, and increased IRS-2 protein levels in the liver. The muscarinic receptor antagonist atropine blocked these effects of physostigmine on liver TG, serum insulin, and hepatic protein levels of SREBP-1 and L-FABP. These results demonstrate that AChE inhibition facilitated fasting-induced TG accumulation with up regulation of the hepatic L-FABP and SREBP-1 in mice, at least in part via the activation of muscarinic acetylcholine receptors. Our studies highlight the crucial role of parasympathetic regulation in fasting-induced TG accumulation, and may be an important source of information on the mechanism of hepatic disorders of lipid metabolism.