Modulation of hepatic transcription factor EB activity during cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids byPla2g15

Abstract

SummaryCold exposure is an environmental stress that elicits a rapid metabolic shift in endotherms and is required for survival. The liver provides metabolic flexibility through its ability to rewire lipid metabolism to respond to an increased demand in energy for thermogenesis. We leveraged cold exposure to identify novel lipids contributing to energy homeostasis and found that lysosomal bis(monoacylglycero)phosphate (BMP) lipids were significantly increased in the liver during acute 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. Through molecular biology and biochemical assays, we found that TFEB regulates lipid catabolism during cold exposure and that TFEB knockdown mice were cold intolerant. To identify how TFEB regulates BMP lipid levels, we used a combinatorial approach to identify TFEB targetPla2g15, a lysosomal phospholipase, as capable of degrading BMP lipids inin vitroliposome assays. Knockdown ofPla2g15in hepatocytes led to a decrease in BMP lipid species. Together, our studies uncover a required role of TFEB in mediating lipid liver remodeling during cold exposure and identifiedPla2g15as an enzyme that regulates BMP lipid catabolism.