Hepatic Levels of DHA-Containing Phospholipids Instruct SREBP1-Mediated Synthesis and Systemic Delivery of Polyunsaturated Fatty Acids
Hepatic Levels of DHA-Containing Phospholipids Instruct SREBP1-Mediated Synthesis and Systemic Delivery of Polyunsaturated Fatty Acids
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DOI：
10.1016/j.isci.2020.101495
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发表时间：
2020-09-25
期刊：
影响因子：
5.8
通讯作者：
Shimizu, Takao
中科院分区：
文献类型：
--
作者：
Hishikawa, Daisuke;Yanagida, Keisuke;Shimizu, Takao
多不饱和脂肪酸（PUFA），如二十二碳六烯酸（DHA）和花生四烯酸（ARA），在哺乳动物生理学中起着重要作用。虽然PUFA失衡会导致各种疾病，但对其全身水平的调节机制知之甚少。在这里，我们报告说，肝DHA含磷脂（DHA-PLs）确定PUFA的全身水平通过SREBP 1介导的转录程序。我们证明了肝脏特异性Agpat 3缺失导致DHA-PL减少和ARA-PL代偿性增加，不仅在肝脏中，而且在包括脑在内的其他组织中。结合血浆溶血磷脂酰胆碱（lysoPC）是脑DHA的主要来源这一最新发现，我们的研究结果表明，肝脏AGPAT 3通过提供DHA-PLs作为DHA-lysoPC的前体而促进脑DHA的积累。此外，膳食鱼油介导的肝脏PUFA生物合成程序的抑制在肝脏特异性Agpat 3缺失中减弱。我们的研究结果强调了肝脏DHA-PLs作为PUFA系统稳态的分子变阻器的核心作用。
Polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) and arachidonic acid (ARA), play fundamental roles in mammalian physiology. Although PUFA imbalance causes various disorders, mechanisms of the regulation of their systemic levels are poorly understood. Here, we report that hepatic DHA-containing phospholipids (DHA-PLs) determine the systemic levels of PUFAs through the SREBP1-mediated transcriptional program. We demonstrated that liver-specific deletion of Agpat3 leads to a decrease of DHA-PLs and a compensatory increase of ARA-PLs not only in the liver but also in other tissues including the brain. Together with recent findings that plasma lysophosphatidylcholine (lysoPC) is themajor source of brain DHA, our results indicate that hepatic AGPAT3 contributes to brain DHA accumulation by supplying DHA-PLs as precursors of DHA-lysoPC. Furthermore, dietary fish oil-mediated suppression of hepatic PUFA biosynthetic program was blunted in liver-specific Agpat3 deletion. Our findings highlight the central role of hepatic DHA-PLs as the molecular rheostat for systemic homeostasis of PUFAs.