Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by phospholipase A2 group XV

Jessica W Davidson¹, Raghav Jain², Thomas Kizzar¹, Gisela Geoghegan¹, Daniel J Nesbitt³, Amy Cavanagh¹, Akira Abe⁴, Kwamina Nyame⁵, Andrea Hunger¹, Xiaojuan Chao⁶, Isabella James¹, Helaina Walesewicz¹, Dominique A Baldwin², Gina Wade¹, Sylwia Michorowska⁷, Rakesh Verma⁴, Kathryn Schueler¹, Vania Hinkovska-Galcheva⁴, Evgenia Shishkova⁸, Wen-Xing Ding⁶, Joshua J Coon⁹, James A Shayman⁴, Monther Abu-Remaileh⁵, Judith A Simcox¹⁰

Affiliations

¹ Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
² Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Howard Hughes Medical Institute, Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
³ Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁴ Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA; The Institute for Chemistry, Engineering & Medicine for Human Health (Sarafan ChEM-H), Stanford University, Stanford, CA 94305, USA.
⁶ Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
⁷ Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Drug Chemistry, Pharmaceutical and Biomedical Analysis, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland.
⁸ Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁹ Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Morgridge Institute for Research, Madison, WI 53715, USA.
¹⁰ Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Howard Hughes Medical Institute, Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: jsimcox@wisc.edu.

PMID: 40373767
PMCID: PMC12136990 (available on 2026-06-03)
DOI: 10.1016/j.cmet.2025.04.015

Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by phospholipase A2 group XV

Jessica W Davidson et al. Cell Metab. 2025.

. 2025 Jun 3;37(6):1413-1425.e6.

doi: 10.1016/j.cmet.2025.04.015. Epub 2025 May 14.

Authors

Affiliations

¹ Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
² Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Howard Hughes Medical Institute, Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
³ Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁴ Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA; The Institute for Chemistry, Engineering & Medicine for Human Health (Sarafan ChEM-H), Stanford University, Stanford, CA 94305, USA.
⁶ Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
⁷ Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Drug Chemistry, Pharmaceutical and Biomedical Analysis, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland.
⁸ Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁹ Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Morgridge Institute for Research, Madison, WI 53715, USA.
¹⁰ Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Howard Hughes Medical Institute, Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: jsimcox@wisc.edu.

PMID: 40373767
PMCID: PMC12136990 (available on 2026-06-03)
DOI: 10.1016/j.cmet.2025.04.015

Abstract

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.

Keywords: BMP; LC-MS; Pla2g15; TFEB; bis(monoacylglycero)phosphate; cold exposure; lipidomics; liquid chromatography-mass spectrometry; liver; lysosome; phospholipase A2 G15; transcription factor EB.

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Conflict of interest statement

Declaration of interests J.J.C. is a consultant for Thermo Fisher Scientific, 908 Devices, and Seer. M.A.-R. is a scientific advisory board member of Lycia Therapeutics and senior advisor of Scenic Biotech.

Update of

Modulation of hepatic transcription factor EB activity during cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by Pla2g15.
Davidson JW, Jain R, Kizzar T, Geoghegan G, Nesbitt DJ, Cavanagh A, Abe A, Nyame K, Hunger A, Chao X, James I, Von Bank H, Baldwin DA, Wade G, Michorowska S, Verma R, Scheuler K, Hinkovska-Galcheva V, Shishkova E, Ding WX, Coon JJ, Shayman JA, Abu-Remaileh M, Simcox JA. Davidson JW, et al. bioRxiv [Preprint]. 2025 Feb 19:2023.11.03.565498. doi: 10.1101/2023.11.03.565498. bioRxiv. 2025. Update in: Cell Metab. 2025 Jun 3;37(6):1413-1425.e6. doi: 10.1016/j.cmet.2025.04.015. PMID: 37986778 Free PMC article. Updated. Preprint.

References

1. Bornstein MR, Neinast MD, Zeng X, Chu Q, Axsom J, Thorsheim C, Li K, Blair MC, Rabinowitz JD, and Arany Z (2023). Comprehensive quantification of metabolic flux during acute cold stress in mice. Cell Metab 35, 2077–2092.e2076. 10.1016/j.cmet.2023.09.002. - DOI - PMC - PubMed
1. Chitraju C, Fischer AW, Farese RV Jr., and Walther TC (2020). Lipid Droplets in Brown Adipose Tissue Are Dispensable for Cold-Induced Thermogenesis. Cell Rep 33, 108348. 10.1016/j.celrep.2020.108348. - DOI - PMC - PubMed
1. Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G, Meyer C, Rozman J, Heldmaier G, Maier R, Theussl C, Eder S, et al. (2006). Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science (New York, N.Y.) 312, 734–737. 10.1126/science.1123965. - DOI - PubMed
1. Schreiber R, Diwoky C, Schoiswohl G, Feiler U, Wongsiriroj N, Abdellatif M, Kolb D, Hoeks J, Kershaw EE, Sedej S, et al. (2017). Cold-Induced Thermogenesis Depends on ATGL-Mediated Lipolysis in Cardiac Muscle, but Not Brown Adipose Tissue. Cell Metab 26, 753–763.e757. 10.1016/j.cmet.2017.09.004. - DOI - PMC - PubMed
1. Jurado-Fasoli L, Sanchez-Delgado G, Di X, Yang W, Kohler I, Villarroya F, Aguilera CM, Hankemeier T, Ruiz JR, and Martinez-Tellez B (2024). Cold-induced changes in plasma signaling lipids are associated with a healthier cardiometabolic profile independently of brown adipose tissue. Cell Rep Med 5, 101387. 10.1016/j.xcrm.2023.101387. - DOI - PMC - PubMed

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Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by phospholipase A2 group XV

Affiliations

Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by phospholipase A2 group XV

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Miscellaneous