Myriocin-mediated up-regulation of hepatocyte apoA-I synthesis is associated with ERK inhibition.
Myriocin-mediated up-regulation of hepatocyte apoA-I synthesis is associated with ERK inhibition.
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DOI：
10.1042/cs20090452
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发表时间：
2010-03-30
期刊：
影响因子：
--
通讯作者：
Garner B
中科院分区：
文献类型：
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作者：
Glaros EN;Kim WS;Garner B
包括鞘磷脂在内的鞘脂类被认为是潜在的致动脉粥样硬化脂质。在apoE（载脂蛋白E）缺失小鼠中的研究表明，丝氨酸棕榈酰转移酶抑制剂myriocin可降低鞘磷脂、神经酰胺、鞘氨醇-1-磷酸和鞘糖脂的血浆水平，这与动脉粥样硬化的有效抑制有关。有趣的是，在用多球壳菌素处理的apoE基因敲除小鼠中，肝脏apoA-I（载脂蛋白A-I）合成和血浆HDL（高密度脂蛋白）胆固醇水平也增加。由于myriocin是一种已知的ERK（细胞外信号相关激酶）磷酸化抑制剂，我们评估了myriocin可能通过该途径增加肝脏apoA-I产生的可能性。为了解决这一问题，用200 μM多球壳菌素处理HepG 2细胞和原代小鼠肝细胞长达48 h。Myriocin增加apoA-I mRNA和蛋白水平约。3-和2倍。多粒壳菌素还增加apoA-I分泌高达3.5倍，并降低ERK磷酸化约。百分之七十从apoE缺失小鼠中分离原代肝细胞时获得了类似的结果，apoE缺失小鼠用多球壳菌素处理（以0.3 mg/kg体重的剂量腹膜内注射）。进一步的实验表明，MEK（丝裂原活化蛋白激酶/ERK激酶）抑制剂PD 98059强效抑制ERK磷酸化，正如预期的那样，并增加原代肝细胞apoA-I的生产3倍。这些结果表明ERK磷酸化在调节肝脏apoA-I表达中起作用，并表明多球壳菌素的抗动脉粥样硬化作用机制可能与此途径有关。
Sphingolipids including sphingomyelin have been implicated as potential atherogenic lipids. Studies in apoE (apolipoprotein E)-null mice have revealed that the serine palmitoyltransferase inhibitor myriocin reduces plasma levels of sphingomyelin, ceramide, sphingosine-1-phosphate and glycosphingolipids and that this is associated with potent inhibition of atherosclerosis. Interestingly, hepatic apoA-I (apolipoprotein A-I) synthesis and plasma HDL (high-density lipoprotein)-cholesterol levels were also increased in apoE-null mice treated with myriocin. Since myriocin is a known inhibitor of ERK (extracellular-signal-related kinase) phosphorylation, we assessed the possibility that myriocin may be acting to increase hepatic apoA-I production via this pathway. To address this, HepG2 cells and primary mouse hepatocytes were treated with 200 μM myriocin for up to 48 h. Myriocin increased apoA-I mRNA and protein levels by approx. 3- and 2-fold respectively. Myriocin also increased apoA-I secretion up to 3.5-fold and decreased ERK phosphorylation by approx. 70%. Similar findings were obtained when primary hepatocytes were isolated from apoE-null mice that were treated with myriocin (intraperitoneal injection at a dose of 0.3 mg/kg body weight). Further experiments revealed that the MEK (mitogen-activated protein kinase/ERK kinase) inhibitor PD98059 potently inhibited ERK phosphorylation, as expected, and increased primary hepatocyte apoA-I production by 3-fold. These results indicate that ERK phosphorylation plays a role in regulating hepatic apoA-I expression and suggest that the anti-atherogenic mechanism of action for myriocin may be linked to this pathway.