Hepatic Levels of DHA-Containing Phospholipids Instruct SREBP1-Mediated Synthesis and Systemic Delivery of Polyunsaturated Fatty Acids
Daisuke Hishikawa,
Keisuke Yanagida,
Katsuyuki Nagata,
Ayumi Kanatani,
Yoshiko Iizuka,
Fumie Hamano,
Megumi Yasuda,
Tadashi Okamura,
Hideo Shindou,
Takao Shimizu
Affiliations
Daisuke Hishikawa
Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan; Corresponding author
Keisuke Yanagida
Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan
Katsuyuki Nagata
Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan
Ayumi Kanatani
Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan
Yoshiko Iizuka
Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan
Fumie Hamano
Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan; Life Science Core Faculty, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
Megumi Yasuda
Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan
Tadashi Okamura
Laboratory Animal Medicine, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan; Section of Animal Models, Department of Infectious Diseases, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan
Hideo Shindou
Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan; Department of Lipid Science, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
Takao Shimizu
Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan; Department of Lipidomics, Graduate School of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; Corresponding author
Summary: 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 the major 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.
