B12 Regulation of PUFA Synthesis

与年龄相关的认知能力下降与神经炎症和氧化应激的增加密切相关。长期饮食缺乏B12和n-3必需脂肪酸也与慢性全身性炎症以及神经炎症有关，这些炎症会导致髓磷脂分解和神经退行性疾病。B12代谢、复杂脂肪酸合成和促炎机制之间存在有趣的联系。B12可能直接或间接调节α-亚麻酸（ALA）转化为复杂的抗炎n-3脂肪酸（如二十碳五烯酸（EPA, 20:5n-3）和二十二碳六烯酸（DHA, 22:6n-3））所需的膳食PUFA的延伸和去饱和，表明B12代谢与n-3 PUFA合成之间存在相互作用。本提案的主要目的是研究维生素B12与n-3多不饱和脂肪酸（PUFAs）联合补充的益处，而不是单独给药，在减少被认为是与年龄相关的神经退行性疾病的基本促炎机制方面。因此，需要验证的具体假设是，B12对于已知具有抗炎功能的长链n-3脂肪酸、EPA和DHA等生物活性脂质的合成和功效是必需的。为了验证这一假设，我们将使用巨噬细胞RAW264.7细胞系的体外模型。第一个具体目标是确定B12或B12和-亚麻酸（ALA）的联合补充是否会影响巨噬细胞的促炎和/或抗炎反应。在第二个目标中，将评估暴露于B12或B12和ALA联合暴露后巨噬细胞中参与PUFA合成的整体延长酶和去饱和酶的表达以及n-3和n-6 PUFAs的浓度。一个预期的结果是，B12和n-3 PUFAs的联合补充可以协同减少炎症。这一发现将支持B12代谢可能通过表观遗传调控PUFA合成途径与炎症机制之间的机制联系。我们预计B12和PUFA合成之间的相互作用不仅局限于炎症细胞，也适用于其他细胞和组织，如乳腺或神经组织，在这些细胞和组织中，复杂的PUFA形成对人体整体健康至关重要。

Age-related cognitive decline is strongly associated with increases in neuro-inflammation and oxidative stress. Long-term dietary deficiencies in both B12 and n-3 essential fatty acids are also associated with chronic systemic inflammation as well as neuro-inflammation contributing to myelin breakdown and neurodegenerative diseases. There are intriguing links between B12 metabolism, complex fatty acid synthesis, and pro-inflammatory mechanisms. B12 might directly or indirectly regulate the elongation and desaturation of dietary PUFAs required for the conversion of dietary α-linolenic acid (ALA) to complex anti-inflammatory n-3 fatty acids such as eicosapentaenoic (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3), suggesting an interaction between B12 metabolism and n-3 PUFA synthesis. The major aims of this proposal are designed to investigate the benefit of combined supplementation of vitamin B12 with n-3 polyunsaturated fatty acids (PUFAs), as opposed to their individual administration, in reducing the basic pro-inflammatory mechanisms thought to underly age-related neurodegenerative disorders. Thus, the specific hypothesis to be tested is that B12 is necessary for the synthesis and efficacy of long chain n-3 fatty acids, EPA and DHA- bioactive lipids with known anti-inflammatory function. To address this hypothesis, an in vitro model using macrophage RAW264.7 cell line will be used. The first specific aim is to address whether B12 or the combined supplementation of B12 and -linolenic acid (ALA) will influence macrophage pro-inflammatory and/or anti-inflammatory responses. In the second aim, the expression of integral elongases and desaturases involved in PUFA synthesis as well as the concentration of n-3 and n-6 PUFAs will be assessed in macrophages following exposure to B12 or the combined exposure of B12 and ALA. One expected outcome would be that combined supplementation of B12 and n-3 PUFAs acts synergistically to reduce inflammation. This finding would support a mechanistic link between B12 metabolism possibly through epigenetic regulation of PUFA synthesis pathways to inflammatory mechanisms. We would expect that this interaction between B12 and PUFA synthesis is not limited to only inflammatory cells but also to other cells and tissues, such as mammary or neuronal tissue, where complex PUFA formation integral to overall human health takes place.