Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by phospholipase A2 group XV
Cold exposure is a selective environmental stress that elicits a rapid metabolic shift to maintain energy homeostasis. In response to cold exposure, the liver rewires the metabolic state, shifting from glucose to lipid catabolism. By probing the liver lipids in cold exposure, we observed that the lysosomal bis(monoacylglycero)phosphate (BMP) lipids were rapidly increased during cold exposure. BMP lipid changes occurred independently of lysosomal abundance but were dependent on the lysosomal transcriptional regulator transcription factor EB (TFEB). Knockdown of Tfeb in hepatocytes decreased BMP lipid levels and led to cold intolerance in mice. We assessed TFEB-binding sites of lysosomal genes and determined that the phospholipase a2 group XV (PLA2G15) regulates BMP lipid catabolism. Decreasing Pla2g15 levels in mice increased BMP lipids, ablated the cold-induced rise in BMP lipids, and improved cold tolerance. Mutation of the catalytic site of PLA2G15 ablated the BMP lipid breakdown. Together, our studies uncover TFEB regulation of BMP lipids through PLA2G15 catabolism.
Authors
- Judith Simcox (ORCID: https://orcid.org/0000-0001-7350-6342)
- Isabella James (ORCID: https://orcid.org/0009-0000-2796-3497)
- Andrea Hunger
- Jessica Davidson
- Daniel J. Nesbitt (ORCID: https://orcid.org/0000-0002-8769-3908)
- Sylwia Michorowska (ORCID: https://orcid.org/0000-0001-7079-7527)
- Kwamina Nyame (ORCID: https://orcid.org/0000-0001-8898-4689)
- Monther Abu-Remaileh (ORCID: https://orcid.org/0000-0003-3772-0477)
- Raghav Jain (ORCID: https://orcid.org/0000-0002-1284-6762)
- Gina Wade (ORCID: https://orcid.org/0009-0000-1773-1393)
- Evgenia Shishkova (ORCID: https://orcid.org/0000-0001-6097-6097)
- James A. Shayman (ORCID: https://orcid.org/0000-0003-3230-0190)
- Xiaojuan Chao (ORCID: https://orcid.org/0000-0002-8731-7785)
- Joshua J. Coon (ORCID: https://orcid.org/0000-0002-0004-8253)
- Amy T. Cavanagh
- Kathryn L. Schueler (ORCID: https://orcid.org/0000-0003-4260-581X)
- Gisela Geoghegan
- Rakesh Kumar Verma (ORCID: https://orcid.org/0000-0002-8984-7587)
- Akira Abe (ORCID: https://orcid.org/0000-0002-0344-2643)
- Vania Hinkovska-Galcheva
- Wen-Xing Ding
- Dominique A. Baldwin
- Thomas Kizzar
- Helaina Walesewicz
Institutions
- University of Wisconsin System (US)
- University of Wisconsin–Madison (US)
- Medical University of Warsaw (PL)
- University of Michigan (US)
- Morgridge Institute for Research (US)
- University of Kansas Medical Center (US)
- Stanford University (US)
Publication Details
- Journal
- Cell Metabolism
- Published
- 2025-05-14
- DOI
- https://doi.org/10.1016/j.cmet.2025.04.015
- Citations
- 10
- Primary Topic
- Lipid metabolism and biosynthesis
- Type
- article
- Field-Weighted Citation Impact
- 11.12