Sex-specific perturbation of complex lipids in response to medium-chain fatty acids in very long-chain acyl-CoA dehydrogenase deficiency.,The FEBS Journal

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Sex-specific perturbation of complex lipids in response to medium-chain fatty acids in very long-chain acyl-CoA dehydrogenase deficiency.
The FEBS Journal ( IF 5.5 ) Pub Date : 2020-01-22 , DOI: 10.1111/febs.15221
Khaled I Alatibi _{1,

2} , Zeinab Wehbe _{1,

2} , Ute Spiekerkoetter ₃ , Sara Tucci ₁

Affiliation

Very‐long‐chain acyl‐CoA dehydrogenase deficiency (VLCAD) is the most common defect of long‐chain fatty acid β‐oxidation. The recommended treatment includes the application of medium‐chain triacylglycerols (MCTs). However, long‐term treatment of VLCAD^−/− mice resulted in the development of a sex‐specific metabolic syndrome due to the selective activation of the ERK/mTORc1 signalling in females and ERK/peroxisome proliferator‐activated receptor gamma pathway in males. In order to investigate a subsequent sex‐specific effect of MCT on the lipid composition of the cellular membranes, we performed lipidomic analysis, SILAC‐based quantitative proteomics and gene expression in fibroblasts from WT and VLCAD^−/− mice of both sexes. Treatment with octanoate (C8) affected the composition of complex lipids resulting in a sex‐specific signature of the molecular profile. The content of ceramides and sphingomyelins in particular differed significantly under control conditions and increased markedly in cells from mutant female mice but remained unchanged in cells from mutant males. Moreover, we observed a specific upregulation of biosynthesis of plasmalogens only in male mice, whereas in females C8 led to the accumulation of higher concentration of phosphatidylcholines and lysophosphatidylcholines. Our data on membrane lipids in VLCAD after supplementation with C8 provide evidence of a sex‐specific lipid perturbation. We hypothesize a likely C8‐induced pro‐inflammatory response contributing to the development of a severe metabolic syndrome in female VLCAD^−/− mice on long‐term MCT supplementation.

中文翻译：

在非常长链的酰基辅酶A脱氢酶缺乏症中，响应中链脂肪酸的复杂脂质的性别特异性扰动。

超长链酰基辅酶A脱氢酶缺乏症（VLCAD）是长链脂肪酸β-氧化的最常见缺陷。推荐的治疗方法包括应用中链三酰基甘油（MCT）。但是，由于雌性动物中ERK / mTORc1信号的选择性激活和雄性中ERK /过氧化物酶体增殖物激活的受体γ途径的选择性激活，VLCAD ^-/-小鼠的长期治疗导致了性别特异性代谢综合征的发展。为了研究MCT对细胞膜脂质成分的后续性别特异性作用，我们在WT和VLCAD的成纤维细胞中进行了脂质组分析，基于SILAC的定量蛋白质组学和基因表达^-/-雌雄同体的老鼠。用辛酸酯（C8）处理会影响复杂脂质的组成，从而导致分子图谱具有性别特异性。神经酰胺和鞘磷脂的含量在对照条件下尤其显着不同，并且在突变雌性小鼠的细胞中明显增加，但在突变雄性小鼠的细胞中保持不变。此外，我们仅在雄性小鼠中观察到缩醛磷脂的生物合成的特定上调，而在雌性中，C8导致较高浓度的磷脂酰胆碱和溶血磷脂酰胆碱的积累。我们关于补充C8后VLCAD中膜脂的数据提供了性别特异性脂微扰的证据。我们假设可能由C8诱导的促炎反应导致女性VLCAD中严重的代谢综合征的发展^-/-长期补充MCT的小鼠。

更新日期：2020-01-22

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