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

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.