Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by phospholipase A2 group XV
Year: 2025
Type: article
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.
Source: Cell Metabolism
Authors: Jessica W. Davidson, Raghav Jain, Thomas Kizzar, Gisela Geoghegan, Daniel J. Nesbitt, Amy Cavanagh, Akira Abe, Kwamina Nyame, Andrea Hunger, Xiaojuan Chao, Isabella James, Helaina Walesewicz, Dominique A. Baldwin, Gina Wade, Sylwia Michorowska, Rakesh Verma, Kathryn Schueler, Vania Hinkovska-Galcheva, Evgenia Shishkova, Wen-Xing Ding, Joshua J. Coon, James A. Shayman, Monther Abu-Remaileh, Judith A. Simcox
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $10,400
Funders: National Science Foundation, Howard Hughes Medical Institute, Pew Charitable Trusts, American Federation for Aging Research, Alexander and Margaret Stewart Trust, Glenn Foundation for Medical Research, National Sleep Foundation, University of Wisconsin-Madison, Juvenile Diabetes Research Foundation United States of America, National Institutes of Health, National Institute of Food and Agriculture, National Institute on Aging, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, JDRF
Awards: Graduate Research Fellowship Program (GRFP), G1501155104, G2097680908, Graduate Research Fellowship Program (GRFP), G6283091259, G8072930897, Biotechnology Training Program, Biology of Aging and Age-Related Diseases, Graduate Training in Molecular and Cellular Pharmacology, National Center for Quantitative Biology of Complex Systems, Institutional Training in the Genomic Sciences, Discovery and characterization of a novel acylcarnitine transporter in brown adipocytes, G956086914
OpenAlex ID: W4410363199