Disruption of de novo fatty acid biosynthesis rewires cellular lipid metabolism toward mTOR-associated compensatory fatty acid uptake
Abstract Upon antigen stimulation, naïve CD4⁺ T cells undergo rapid metabolic remodeling that supports immune responses. Lipid metabolism has emerged as a critical regulator of T-cell proliferation, effector function, and memory formation, and has been proposed as a potential therapeutic target in immune-related diseases. However, how T cells adapt to perturbation in lipid metabolism remains unclear. To address this question, we performed integrative multi-omics analyses in EL4 T cells, including transcriptomics, proteomics, phosphoproteomics, and lipidomics, to investigate metabolic adaptation under conditions of impaired fatty acid biosynthesis. In EL4 T cells, disruption of acetyl-CoA carboxylase 1 (ACC1), a rate-limiting enzyme of fatty acid biosynthesis, reduced lipid droplet abundance and enhanced fatty acid uptake. Transcriptomic and proteomic analyses revealed upregulation of fatty acid transporters such as CD36 and SLC27A4, and functional disruption of these transporters attenuated the increased fatty acid uptake. Lipidomic analysis further showed widespread reductions in neutral lipid species and increased phospholipid unsaturation. Moreover, phosphoproteomic analysis implicated the mTOR signaling pathway, and pharmacological inhibition of mTOR suppressed the elevated fatty acid uptake in ACC1-deficient cells. Collectively, these findings reveal unrecognized mechanisms of lipid metabolic adaptation and highlight a regulatory network that coordinates fatty acid uptake in response to impaired lipid synthesis.
Authors
- Takaharu Kimura (ORCID: https://orcid.org/0000-0002-1642-2908)
- Keisuke Yamamoto (ORCID: https://orcid.org/0000-0002-6323-9540)
- Yusuke Kawashima (ORCID: https://orcid.org/0000-0002-9779-8199)
- Yusuke Endo (ORCID: https://orcid.org/0000-0002-7223-1938)
- Toshio Kanno (ORCID: https://orcid.org/0000-0002-7586-8723)
- Toshiyuki Kobayashi (ORCID: https://orcid.org/0000-0003-0671-5886)
- Keisuke Miyako (ORCID: https://orcid.org/0009-0000-6533-2979)
- Keiko Nakano (ORCID: https://orcid.org/0000-0003-2735-4119)
- Osamu Ohara (ORCID: https://orcid.org/0000-0002-3328-9571)
- Kazuko Yamada
- Hikari K. Asou (ORCID: https://orcid.org/0000-0002-2701-5953)
- Arisa Ito (ORCID: https://orcid.org/0000-0002-5518-1078)
- Ryo Konno (ORCID: https://orcid.org/0000-0002-9403-1339)
- Takeru Endo
- Souta Yoshida
- Satoru Yokoyama
Institutions
- Chiba University (JP)
- Kazusa DNA Research Institute (JP)
Publication Details
- Journal
- Scientific Reports
- Published
- 2026-08-26
- DOI
- https://doi.org/10.1038/s41598-026-68763-5
- Primary Topic
- Fatty Acid Research and Health
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Canon Foundation in Europe
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- Research Promotion Foundation
- Kato Memorial Bioscience Foundation
- Astellas Pharma
- Shionogi
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Cosmetology Research Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Ono Medical Research Foundation
- Yasuda Memorial Medical Foundation
- Princess Takamatsu Cancer Research Fund
- Nagase Science Technology Foundation
- Ono Pharmaceutical
- Toray Science Foundation
- Core Research for Evolutional Science and Technology
- Fusion Oriented REsearch for disruptive Science and Technology