Miltefosine Suppresses Hepatic Steatosis by Activating AMPK Signal Pathway.
Miltefosine Suppresses Hepatic Steatosis by Activating AMPK Signal Pathway.
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米替福辛通过激活 AMPK 信号通路抑制肝脏脂肪变性
DOI：
10.1371/journal.pone.0163667
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Chen Q
中科院分区：
文献类型：
--
作者：
Fang R;Zhu X;Zhu Y;Tong X;Li K;Bai H;Li X;Ben J;Zhang H;Yang Q;Chen Q
AMPK（腺苷单磷酸活化蛋白激酶）激活对糖脂代谢具有许多有益的作用。溶血磷脂酰胆碱（LPC）是一种重要的溶血磷脂，通过激活巨噬细胞AMPK信号通路，可改善糖尿病小鼠血糖水平，减轻炎症反应。合成烷基磷脂（ALP），如米替福新，被用作临床应用的LPC替代品。在这里，我们调查了米替福新是否会对肝脂肪变性和相关代谢紊乱产生影响。用高脂饮食（HFD）喂养小鼠16周以产生肥胖模型。接下来，将肥胖小鼠随机分为三组：生理盐水治疗组和米替膦治疗组（2.5或5 mg/kg/d）。将米替福新腹膜内给予小鼠另外4周加HFD治疗。研究表明，米替福新治疗可以通过激活AMPK信号通路，显着改善HFD喂养小鼠的葡萄糖代谢，防止肝脏脂质积聚，并抑制肝脏炎症。在体外实验中，米替福新以时间和剂量依赖性方式刺激AMPKα磷酸化，并减少肝细胞脂质蓄积。当使用特异性AMPK抑制剂化合物C治疗小鼠时，米替福新对HFD诱导的小鼠脂肪酸血症和肝脏脂肪变性的拮抗作用被消除。米替福新治疗还显著抑制HFD诱导的小鼠肝脏炎症。本研究表明米替福新可能是一种新的AMPK信号通路激活剂，在体内外实验中可用于治疗脂肪肝及相关代谢紊乱。
It has been accepted that AMPK (Adenosine monophosphate–activated protein kinase) activation exhibits many beneficial effects on glucolipid metabolism. Lysophosphatidylcholine (LPC) is an important lysophospholipid which can improve blood glucose levels in diabetic mice and attenuate inflammation by activating AMPK signal pathway in macrophages. Synthetic alkylphospholipids (ALPs), such as miltefosine, is used as an alternate of LPC for the clinical application. Here, we investigated whether miltefosine could have an impact on hepatic steatosis and related metabolic disorders. Mice were fed with high fat diet (HFD) for 16 weeks to generate an obese model. Next, the obese mice were randomly divided into three groups: saline-treated and miltefosine-treated (2.5 or 5 mg/kg/d) groups. Miltefosine was intraperitoneally administrated into mice for additional 4 weeks plus HFD treatment. It was shown that miltefosine treatment could substantially improve glucose metabolism, prevented hepatic lipid accumulation, and inhibited liver inflammation in HFD-fed mice by activating AMPK signal pathway. In vitro, miltefosine stimulated AMPKα phosphorylation both in time and dose dependent manner and decreased lipid accumulation in liver cells. When a specific AMPK inhibitor compound C was used to treat mice, the antagonistic effects of miltefosine on HFD-induced mouse hyperlipidaemia and liver steatosis were abolished. Treatment with miltefosine also dramatically inhibited the HFD-induced liver inflammation in mice. Here we demonstrated that miltefosine might be a new activator of AMPK signal pathway in vivo and in vitro and be useful for treatment of hepatic steatosis and related metabolic disorders.
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