Fenofibrate lowers atypical sphingolipids in plasma of dyslipidemic patients: A novel approach for treating diabetic neuropathy?
Fenofibrate lowers atypical sphingolipids in plasma of dyslipidemic patients: A novel approach for treating diabetic neuropathy?
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DOI：
10.1016/j.jacl.2015.03.011
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发表时间：
2015-08-01
影响因子：
4.4
通讯作者：
Hornemann, Thorsten
中科院分区：
文献类型：
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作者：
Othman, Alaa;Benghozi, Renee;Hornemann, Thorsten
背景：棕榈酰辅酶a和l-丝氨酸的缩合是鞘脂重新形成的第一步，并由丝氨酸-棕榈酰转移酶（SPT）催化。除其他酰基辅酶a外，SPT还能代谢l-丙氨酸和甘氨酸，形成非典型的神经毒性1-脱氧鞘脂（1-deoxySL）。SPT中的一些突变与病理性1-脱氧ysl水平升高有关，从而导致遗传性感觉神经病变HSAN1。1-脱氧ysl水平在代谢综合征和II型糖尿病患者中也升高，似乎与糖尿病神经病变的病理有关。目的：在之前的研究中，我们观察到血浆1-脱氧ysl和甘油三酯（TGs）之间有很强的相关性。因此，我们感兴趣的是降低血浆TG水平是否也会影响血浆鞘脂，特别是1-脱氧ysl水平。方法：66例血脂异常患者使用降tg药物非诺贝特（160 mg/d）或缓释烟酸（0.5 g/d， 3周，然后1 g/d）治疗6周，两次治疗之间有4周的洗脱期。采用液相色谱-质谱（LC-MS）分析各治疗块前后的括约肌碱谱。结果：非诺贝特显著降低1-脱氧ysl和其他非典型鞘基(P
BACKGROUND: The condensation of palmitoyl-CoA and L-Serine is the first step in the de novo formation of sphingolipids and catalyzed by the serine-palmitoyltransferase (SPT). Besides other acyl-CoAs the SPT can also metabolize L-alanine and glycine, which forms an atypical category of neurotoxic 1-deoxy-sphingolipids (1-deoxySL). Several mutations in SPT are associated with pathologically increased 1-deoxySL levels, which cause the inherited sensory neuropathy HSAN1. 1-DeoxySL levels are also elevated in individuals with the metabolic syndrome and diabetes mellitus type II and seem to be involved in the pathology of the diabetic neuropathy.OBJECTIVE: In previous studies, we observed a strong correlation between plasma 1-deoxySLs and triglycerides (TGs). We were therefore interested whether lowering plasma TG levels also affects plasma sphingolipid and in particular, 1-deoxySL levels.METHODS: Sixty-six patients with dyslipidemia were treated for 6 wk with the TG-lowering drug fenofibrate (160 mg/d) or extended-release niacin (0.5 g/d for 3 wk, then 1 g/d) with 4 wk of washout between treatments. The sphingoid base profile was analyzed by liquid chromatography-mass spectrometry (LC-MS) before and after each treatment block. RESULTS: Fenofibrate significantly lowered 1-deoxySLs and other atypical sphingoid bases (P