Department of Psychiatry, Columbia University, New York, NY, USA.
Molecular Imaging & Neuropathology Area, New York State Psychiatric Institute, New York, NY, USA.
Mol Psychiatry. 2024 Feb;29(2):269-286. doi: 10.1038/s41380-023-02322-6. Epub 2023 Nov 22.
Long-chain polyunsaturated fatty acids (LC-PUFAs) are obtained from diet or derived from essential shorter-chain fatty acids, and are crucial for brain development and functioning. Fundamentally, LC-PUFAs' neurobiological effects derive from their physicochemical characteristics, including length and double bond configuration, which differentiate LC-PUFA species and give rise to functional differences between n(omega)-3 and n-6 LC-PUFAs. LC-PUFA imbalances are implicated in psychiatric disorders, including major depression and suicide risk. Dietary intake and genetic variants in enzymes involved in biosynthesis of LC-PUFAs from shorter chain fatty acids influence LC-PUFA status. Domains impacted by LC-PUFAs include 1) cell signaling, 2) inflammation, and 3) bioenergetics. 1) As major constituents of lipid bilayers, LC-PUFAs are determinants of cell membrane properties of viscosity and order, affecting lipid rafts, which play a role in regulation of membrane-bound proteins involved in cell-cell signaling, including monoaminergic receptors and transporters. 2) The n-3:n-6 LC-PUFA balance profoundly influences inflammation. Generally, metabolic products of n-6 LC-PUFAs (eicosanoids) are pro-inflammatory, while those of n-3 LC-PUFAs (docosanoids) participate in the resolution of inflammation. Additionally, n-3 LC-PUFAs suppress microglial activation and the ensuing proinflammatory cascade. 3) N-3 LC-PUFAs in the inner mitochondrial membrane affect oxidative stress, suppressing production of and scavenging reactive oxygen species (ROS), with neuroprotective benefits. Until now, this wealth of knowledge about LC-PUFA biomechanisms has not been adequately tapped to develop translational studies of LC-PUFA clinical effects in humans. Future studies integrating neurobiological mechanisms with clinical outcomes may suggest ways to identify depressed individuals most likely to respond to n-3 LC-PUFA supplementation, and mechanistic research may generate new treatment strategies.
长链多不饱和脂肪酸 (LC-PUFA) 可从饮食中获得或由必需的短链脂肪酸衍生而来，对大脑发育和功能至关重要。从根本上讲，LC-PUFA 的神经生物学作用源自其理化特性，包括长度和双键构型，这些特性区分了 LC-PUFA 种类，并导致 n(ω)-3 和 n-6 LC-PUFA 之间的功能差异。LC-PUFA 失衡与包括重度抑郁症和自杀风险在内的精神疾病有关。LC-PUFA 的饮食摄入和参与从短链脂肪酸生物合成 LC-PUFA 的酶的遗传变异影响 LC-PUFA 状态。LC-PUFA 影响的域包括 1) 细胞信号转导、2) 炎症和 3) 生物能量学。1) 作为脂质双层的主要成分，LC-PUFA 决定了细胞膜的粘度和有序性，影响脂筏，脂筏在调节参与细胞间信号转导的膜结合蛋白中起作用，包括单胺能受体和转运体。2) n-3:n-6 LC-PUFA 平衡对炎症有深远影响。通常，n-6 LC-PUFA（类二十烷酸）的代谢产物具有促炎作用，而 n-3 LC-PUFA（二十二碳六烯酸）则参与炎症的解决。此外，n-3 LC-PUFA 可抑制小胶质细胞激活和随之而来的促炎级联反应。3) 内线粒体膜中的 n-3 LC-PUFA 影响氧化应激，抑制活性氧物质 (ROS) 的产生和清除，具有神经保护作用。到目前为止，LC-PUFA 生物力学方面的大量知识尚未得到充分利用，无法开发 LC-PUFA 对人类临床效果的转化研究。将神经生物学机制与临床结果相结合的未来研究可能会提出一些方法，以确定最有可能对 n-3 LC-PUFA 补充做出反应的抑郁个体，并进行机制研究可能会产生新的治疗策略。
