Characterization of the sex specific metabolic phenotype in very-long chain acyl-CoA dehydrogenase deficient (VLCAD-/-) mice

极长链酰基辅酶 A 脱氢酶缺陷 (VLCAD-/-) 小鼠性别特异性代谢表型的表征

• 批准号: 410964249
• 负责人: Privatdozentin Dr. Sara Tucci
• 金额: --
• 依托单位: Klinikumsapotheke
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/410964249?language=en
• 关键词: Characterization; sex; specific; metabolic; phenotype

Very-long chain acyl-CoA dehydrogenase deficiency is the most common disorder of mitochondrial long-chain fatty acid oxidation with an incidence of 1:50,000-1:100,000 newborns. Catabolic situations contribute to the aggravation of the symptoms and may induce severe metabolic derangement and death. Treatment for VLCAD deficiency includes avoidance of prolonged fasting and a long-chain fat-restricted and fat-modified diet in which long-chain fatty acids (LCFA) are fully or in part replaced by medium-chain triglycerides (MCT). There are no data for humans on the long-term clinical course of the disease and on the role played by sex within phenotype development. Our own results clearly indicate a sexually dimorphic response due to a defective β-oxidation machinery in the mTOR signaling leading to differences in the metabolic adaptation between male and female VLCAD-/- mice. Moreover, lipogenesis was strongly up-regulating in female VLCAD-/- mice and this effect was exacerbated by supplementation with MCT. This is of interest as MCT is widely applied as recommended therapy in the treatment of long-chain fatty acid oxidation disorders and in other diseases such as chyluria, chylotorax and cystic fibrosis as well as for absorption disorders and celiac diseases. Although such differences in patients have not yet been reported, no studies have been conducted in humans with regard to the sexually dimorphic metabolic features or signaling pathways. My hypothesis is that the concomitant effect of a deficient β-oxidation pathway and the supplementation with dietary MCT may contributes to the disturbed signaling cascade via mTOR-PPARγ axis resulting in the development of a sex specific metabolic phenotype.How MCT affects signaling pathway and the regulation of energy metabolism in a sex specific manner, is still unknown. These studies will complement our knowledge on molecular mechanisms which may be involved in the development of symptoms from a point of view not taken into consideration yet.This proposal will address the following aims:- Characterization of the sex specific metabolic phenotype - To explore the role of mTOR/ PPARγ signaling and the effect of MCT in the regulation of energy metabolismWe will, here, clarify whether i) sex may be considered an important variable to take into account in the prospective developing phenotype and ii) whether/ how a diet based on MCT affects signaling pathway and whole-body energy metabolism.

超长链酰辅酶A脱氢酶缺乏症是最常见的线粒体长链脂肪酸氧化障碍，新生儿发病率为1：50,000-1：100,000。分解代谢的情况会加重症状，并可能导致严重的代谢紊乱和死亡。VLCAD缺乏症的治疗包括避免长时间的禁食和长链脂肪限制和脂肪修饰的饮食，其中长链脂肪酸(LCFA)完全或部分被中链甘油三酯(MCT)取代。关于人类疾病的长期临床病程以及性别在表型发育中所起的作用，目前还没有数据。我们自己的结果清楚地表明，由于mTOR信号中β氧化机制的缺陷，导致了雄性和雌性VLCAD-/-小鼠之间代谢适应的差异，从而导致了性二态反应。此外，雌性VLCAD-/-小鼠的脂肪生成强烈上调，补充MCT加剧了这种影响。这一点令人感兴趣，因为MCT作为推荐疗法被广泛应用于治疗长链脂肪酸氧化障碍以及其他疾病，如乳糜尿、乳糜胸和囊性纤维化，以及吸收障碍和乳糜泻。虽然患者之间的这种差异还没有报道，但还没有关于人类性二型性代谢特征或信号通路的研究。我的假设是，缺乏β氧化途径的伴随效应和补充膳食中的MCT可能通过γ轴参与了信号通路的紊乱，导致了性别特异性代谢表型的发展。目前尚不清楚MCT如何以性别特异性的方式影响信号通路和能量代谢的调节。这些研究将从尚未考虑的角度补充我们对症状发生中可能涉及的分子机制的知识。这项建议将解决以下目标：-性别特异性代谢表型的表征-探索mTOR/PPARγ信号的作用和mCT在能量代谢调节中的作用在这里，我们将澄清：i)性别是否可以被认为是未来发展表型中考虑的一个重要变量；ii)基于mct的饮食是否/如何影响信号通路和全身能量代谢。