Hepatic Levels of DHA-Containing Phospholipids Instruct SREBP1-Mediated Synthesis and Systemic Delivery of Polyunsaturated Fatty Acids
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...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-09-01
|
| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004220306878 |
| _version_ | 1818380787454574592 |
|---|---|
| author | Daisuke Hishikawa Keisuke Yanagida Katsuyuki Nagata Ayumi Kanatani Yoshiko Iizuka Fumie Hamano Megumi Yasuda Tadashi Okamura Hideo Shindou Takao Shimizu |
| author_facet | Daisuke Hishikawa Keisuke Yanagida Katsuyuki Nagata Ayumi Kanatani Yoshiko Iizuka Fumie Hamano Megumi Yasuda Tadashi Okamura Hideo Shindou Takao Shimizu |
| author_sort | Daisuke Hishikawa |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T02:24:14Z |
| format | Article |
| id | doaj.art-024f480d745d4c72a1e9ecb0107ecbd8 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-14T02:24:14Z |
| publishDate | 2020-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-024f480d745d4c72a1e9ecb0107ecbd82022-12-21T23:20:25ZengElsevieriScience2589-00422020-09-01239101495Hepatic Levels of DHA-Containing Phospholipids Instruct SREBP1-Mediated Synthesis and Systemic Delivery of Polyunsaturated Fatty AcidsDaisuke Hishikawa0Keisuke Yanagida1Katsuyuki Nagata2Ayumi Kanatani3Yoshiko Iizuka4Fumie Hamano5Megumi Yasuda6Tadashi Okamura7Hideo Shindou8Takao Shimizu9Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan; Corresponding authorDepartment of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, JapanDepartment of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, JapanDepartment of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, JapanDepartment of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, JapanDepartment 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, JapanDepartment of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, JapanLaboratory 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, JapanDepartment 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, JapanDepartment 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004220306878Cellular PhysiologyMolecular PhysiologyMolecular Biology |
| spellingShingle | Daisuke Hishikawa Keisuke Yanagida Katsuyuki Nagata Ayumi Kanatani Yoshiko Iizuka Fumie Hamano Megumi Yasuda Tadashi Okamura Hideo Shindou Takao Shimizu Hepatic Levels of DHA-Containing Phospholipids Instruct SREBP1-Mediated Synthesis and Systemic Delivery of Polyunsaturated Fatty Acids iScience Cellular Physiology Molecular Physiology Molecular Biology |
| title | Hepatic Levels of DHA-Containing Phospholipids Instruct SREBP1-Mediated Synthesis and Systemic Delivery of Polyunsaturated Fatty Acids |
| title_full | Hepatic Levels of DHA-Containing Phospholipids Instruct SREBP1-Mediated Synthesis and Systemic Delivery of Polyunsaturated Fatty Acids |
| title_fullStr | Hepatic Levels of DHA-Containing Phospholipids Instruct SREBP1-Mediated Synthesis and Systemic Delivery of Polyunsaturated Fatty Acids |
| title_full_unstemmed | Hepatic Levels of DHA-Containing Phospholipids Instruct SREBP1-Mediated Synthesis and Systemic Delivery of Polyunsaturated Fatty Acids |
| title_short | Hepatic Levels of DHA-Containing Phospholipids Instruct SREBP1-Mediated Synthesis and Systemic Delivery of Polyunsaturated Fatty Acids |
| title_sort | hepatic levels of dha containing phospholipids instruct srebp1 mediated synthesis and systemic delivery of polyunsaturated fatty acids |
| topic | Cellular Physiology Molecular Physiology Molecular Biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004220306878 |
| work_keys_str_mv | AT daisukehishikawa hepaticlevelsofdhacontainingphospholipidsinstructsrebp1mediatedsynthesisandsystemicdeliveryofpolyunsaturatedfattyacids AT keisukeyanagida hepaticlevelsofdhacontainingphospholipidsinstructsrebp1mediatedsynthesisandsystemicdeliveryofpolyunsaturatedfattyacids AT katsuyukinagata hepaticlevelsofdhacontainingphospholipidsinstructsrebp1mediatedsynthesisandsystemicdeliveryofpolyunsaturatedfattyacids AT ayumikanatani hepaticlevelsofdhacontainingphospholipidsinstructsrebp1mediatedsynthesisandsystemicdeliveryofpolyunsaturatedfattyacids AT yoshikoiizuka hepaticlevelsofdhacontainingphospholipidsinstructsrebp1mediatedsynthesisandsystemicdeliveryofpolyunsaturatedfattyacids AT fumiehamano hepaticlevelsofdhacontainingphospholipidsinstructsrebp1mediatedsynthesisandsystemicdeliveryofpolyunsaturatedfattyacids AT megumiyasuda hepaticlevelsofdhacontainingphospholipidsinstructsrebp1mediatedsynthesisandsystemicdeliveryofpolyunsaturatedfattyacids AT tadashiokamura hepaticlevelsofdhacontainingphospholipidsinstructsrebp1mediatedsynthesisandsystemicdeliveryofpolyunsaturatedfattyacids AT hideoshindou hepaticlevelsofdhacontainingphospholipidsinstructsrebp1mediatedsynthesisandsystemicdeliveryofpolyunsaturatedfattyacids AT takaoshimizu hepaticlevelsofdhacontainingphospholipidsinstructsrebp1mediatedsynthesisandsystemicdeliveryofpolyunsaturatedfattyacids |