PDF(Pubmed)
Abstract：
There is a \"popular\" belief that a fat-free diet is beneficial, supported by the scientific dogma indicating that high levels of fatty acids promote many pathological metabolic, cardiovascular, and neurodegenerative conditions. This dogma pressured scientists not to recognize the essential role of fatty acids in cellular metabolism and focus on the detrimental effects of fatty acids. In this work, we critically review several decades of studies and recent publications supporting the critical role of mitochondrial fatty acid metabolism in cellular homeostasis and many pathological conditions. Fatty acids are the primary fuel source and essential cell membrane building blocks from the origin of life. The essential cell membranes phospholipids were evolutionarily preserved from the earlier bacteria in human subjects. In the past century, the discovery of fatty acid metabolism was superseded by the epidemic growth of metabolic conditions and cardiovascular diseases. The association of fatty acids and pathological conditions is not due to their \"harmful\" effects but rather the result of impaired fatty acid metabolism and abnormal lifestyle. Mitochondrial dysfunction is linked to impaired metabolism and drives multiple pathological conditions. Despite metabolic flexibility, the loss of mitochondrial fatty acid oxidation cannot be fully compensated for by other sources of mitochondrial substrates, such as carbohydrates and amino acids, resulting in a pathogenic accumulation of long-chain fatty acids and a deficiency of medium-chain fatty acids. Despite popular belief, mitochondrial fatty acid oxidation is essential not only for energy-demanding organs such as the heart, skeletal muscle, and kidneys but also for metabolically \"inactive\" organs such as endothelial and epithelial cells. Recent studies indicate that the accumulation of long-chain fatty acids in specific organs and tissues support the impaired fatty acid oxidation in cell- and tissue-specific fashion. This work, therefore, provides a basis to challenge these established dogmas and articulate the need for a paradigm shift from the \"pathogenic\" role of fatty acids to the critical role of fatty acid oxidation. This is important to define the causative role of impaired mitochondrial fatty acid oxidation in specific pathological conditions and develop novel therapeutic approaches targeting mitochondrial fatty acid metabolism.
摘要：
有一种“流行”的观点认为无脂肪饮食是有益的，由科学教条支持，表明高水平的脂肪酸促进许多病理性代谢，心血管,和神经退行性疾病。这种教条迫使科学家们不要认识到脂肪酸在细胞代谢中的重要作用，而要关注脂肪酸的有害影响。在这项工作中,我们批判性地回顾了几十年来支持线粒体脂肪酸代谢在细胞稳态和许多病理状况中的关键作用的研究和最近的出版物。脂肪酸是生命起源的主要燃料来源和必需的细胞膜构件。从人类受试者的早期细菌中进化保存了必需的细胞膜磷脂。在过去的一个世纪里,脂肪酸代谢的发现被代谢状况和心血管疾病的流行增长所取代。脂肪酸和病理状况的关联不是由于它们的“有害”效应，而是脂肪酸代谢受损和生活方式异常的结果。线粒体功能障碍与代谢受损有关，并驱动多种病理状况。尽管代谢灵活，线粒体脂肪酸氧化的损失不能被其他来源的线粒体底物完全补偿，如碳水化合物和氨基酸，导致长链脂肪酸的致病性积累和中链脂肪酸的缺乏。尽管普遍相信，线粒体脂肪酸氧化不仅对心脏等需要能量的器官至关重要，骨骼肌,和肾脏，但也用于代谢“非活性”器官，如内皮细胞和上皮细胞。最近的研究表明，长链脂肪酸在特定器官和组织中的积累支持以细胞和组织特异性方式受损的脂肪酸氧化。这项工作,因此,提供了挑战这些既定教条的基础，并阐明了从脂肪酸的“致病性”作用到脂肪酸氧化的关键作用的范式转变的必要性。这对于定义受损的线粒体脂肪酸氧化在特定病理状况中的致病作用和开发靶向线粒体脂肪酸代谢的新型治疗方法是重要的。
