Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics and Adolescent Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Mathildenstrasse 1, Freiburg, Germany; University of Freiburg, Faculty of Biology, Schaenzlestrasse 1, D-79104 Freiburg, Germany.
Department of Molecular Immunology, Institute of Biology III at the Faculty of Biology, Albert-Ludwigs-University of Freiburg, Schänzlestr. 1, 79104 Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS, Albert-Ludwigs-University of Freiburg, Schänzlestr. 18, 79104 Freiburg, Germany.
Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Nov;1864(11):1591-1605. doi: 10.1016/j.bbalip.2019.08.001. Epub 2019 Aug 5.
Medium-chain-triglycerides (MCT) are widely applied in the treatment of long-chain fatty acid oxidation disorders (lcFAOD). Long-term treatment with MCT led to a sexually dimorphic response in the mouse model of very-long-chain-acyl-CoA-dehydrogenase-deficiency (VLCAD) with the subsequent development of a metabolic syndrome in female mice. In order to evaluate the molecular mechanisms responsible for this sex specific response we performed a comprehensive metabolic phenotyping, SILAC-based quantitative proteomics and characterized the involved signaling pathways by western blot analysis and gene expression. WT and VLCAD mice showed strong sex-dependent differences in basal metabolism and expression of proteins involved in the distinct metabolic pathways, even more prominent after treatment with octanoate. The investigation of molecular mechanisms responsible for the sexual dimorphisms delineated the selective activation of the ERK/mTORc1 signaling pathway leading to an increased biosynthesis and elongation of fatty acids in VLCAD females. In contrast, octanoate induced the activation of ERK/PPARγ pathway and the subsequent upregulation of peroxisomal β‑oxidation in males. We here provide first evidence that sex has to be considered as important variable in disease phenotype. These findings may have implications on treatment strategies in the different sexes.
中链甘油三酯（MCT）广泛应用于长链脂肪酸氧化障碍（lcFAOD）的治疗。在长链酰基辅酶 A 脱氢酶缺乏症（VLCAD）的小鼠模型中，长期使用 MCT 导致了一种性别二态性反应，随后雌性小鼠出现了代谢综合征。为了评估导致这种性别特异性反应的分子机制，我们进行了全面的代谢表型分析、SILAC 定量蛋白质组学，并通过 Western blot 分析和基因表达来描述相关的信号通路。WT 和 VLCAD 小鼠在基础代谢和参与不同代谢途径的蛋白质表达方面表现出强烈的性别依赖性差异，在用辛酸盐处理后更为明显。对导致性别二态性的分子机制的研究阐明了 ERK/mTORc1 信号通路的选择性激活，导致 VLCAD 雌性小鼠脂肪酸的生物合成和延长增加。相比之下，辛酸盐诱导 ERK/PPARγ 通路的激活，随后导致雄性小鼠过氧化物酶体β-氧化的上调。我们在此首次提供证据表明，性别必须被视为疾病表型的重要变量。这些发现可能对不同性别中的治疗策略具有重要意义。
