B12 Regulation of PUFA Synthesis

B12 PUFA 合成的调控

• 批准号: 10042751
• 负责人: MICHAEL D WHEELER
• 金额: $ 7.55万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10042751
• 关键词: Address; Age-associated memory impairment; Aging; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Anti-Inflammatory Agents; Attention; Brain; Cell Line; Cells; Chronic; Clinical Management; Clinical Research; Complex; Dementia; Diet; Disease; Disease Progression; Docosahexaenoic Acids; Dose; Eicosapentaenoic Acid; Elderly; Enzymes; Equilibrium; Essential Fatty Acids; Exhibits; Exposure to; Fatty Acids; Flavonoids; Foundations; Fractalkine; Health; Hour; Human; IL4 gene; Immune; Impaired cognition; In Vitro; Individual; Inflammaging; Inflammation; Inflammatory; Inflammatory Response; Interferons; Link; Linolenic Acids; Lipids; Malnutrition; Mammary gland; Metabolism; Myelin; N-3 polyunsaturated fatty acid; Nerve Tissue; Neurodegenerative Disorders; Neurons; Non-Steroidal Anti-Inflammatory Agents; Nutrient; Omega-3 Fatty Acids; Outcome; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Pharmacology; Phenotype; Polyunsaturated Fatty Acids; Population; Process; Production; Psyche structure; Regulation; Reporting; Research Design; Sterility; Supplementation; TNF gene; Testing; Tissues; Vitamin B 12; Vitamin Deficiency; age related; age related cognitive disorder; age related neurodegeneration; aging brain; alpha-Linolenic Acid; autocrine; base; cytokine; desaturase; design; epigenetic regulation; experimental study; gray matter; improved; in vitro Model; macrophage; metabolic profile; myelination; neuroinflammation; paracrine; response; treatment strategy

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.

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，长期饮食中缺乏 B12 和 n-3 必需脂肪酸也与慢性全身炎症以及导致髓磷脂分解的神经炎症有关。 B12 代谢、复杂脂肪酸合成和促炎机制之间存在着有趣的联系，B12 可能直接或间接调节饮食中 PUFA 的伸长和去饱和。膳食 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)，表明 B12 之间存在相互作用该提案的主要目的是研究维生素 B12 与 n-3 多不饱和脂肪酸联合补充的益处。 （PUFA），而不是单独施用，可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。因此，要测试的具体假设是 B12 对于长链 n 的合成和功效是必需的。 -3 脂肪酸、EPA 和 DHA 生物活性脂质具有已知的抗炎功能 为了解决这一假设，将使用使用巨噬细胞 RAW264.7 细胞系的体外模型，第一个具体目标是确定 B12 还是 B12。联合补充 B12 和 α-亚麻酸 (ALA) 将影响巨噬细胞的促炎和/或抗炎反应。第二个目标是影响 PUFA 合成中整体延伸酶和去饱和酶的表达以及 n-3 的浓度。接触 B12 或联合接触 B12 和 ALA 后，将在巨噬细胞中评估 n-6 多不饱和脂肪酸，其中一个预期结果是联合补充 B12 和 n-3。 PUFA 具有协同作用，可减轻炎症。这一发现可能通过 PUFA 合成途径与炎症机制的表观遗传调节来支持 B12 代谢之间的机制联系。我们预计 B12 和 PUFA 合成之间的这种相互作用不仅限于炎症细胞。其他细胞和组织，例如乳腺或神经组织，其中发生复杂的 PUFA 形成，对人类整体健康至关重要。