Acute cold exposure is a selective metabolic pressure that causes rapid, systemic lipid remodeling in mammals. The liver regulates this process through fatty acid uptake, complex lipid anabolism and lipid secretion to fuel thermogenesis. To determine the extent of hepatic lipid alteration in response to cold exposure, we performed global lipidomics on cold exposed mice and observed an increase in lysosomal lipids known as bis(monoacylglycero)phosphates (BMPs). BMP-lipids are known to act as scaffolds for lysosomal hydrolases and regulate lysosomal function, but their significance in cold stress is unknown. To understand the role of hepatic lysosomes in cold, we explored lysosomal abundance during cold exposure. Electron microscopy of cold exposed murine liver showed increased lipid droplet formation compared to room temperature mice. Though lysosomal number was unchanged, lysosomal size and lipid droplet localization was increased, indicative of lysosomal lipophagy.  We sought to determine how lysosomal lipid processing was regulated with cold and examined transcription factor EB (TFEB), a known regulator of lysosomal function and lipid metabolism. ChIP-seq of TFEB demonstrated a remarkable shift in genomic occupancy with 7535 sites lost during cold and only 35 sites gained. Gene ontology indicated TFEB regulation of numerous catabolic processes at RT whereas in cold, only a handful were retained including triglyceride metabolism, polyunsaturated fatty acid synthesis, and glycerophospholipid catabolism. Together, these data demonstrate that TFEB is a major regulator of hepatic lipid remodeling during acute cold exposure, and have broad implications for uncovering a novel TFEB regulatory axis that impacts lipid homeostasis. We will use this system to understand the mechanisms that regulate hepatic TFEB activity and BMP-lipid abundance.

Hepatic TFEB regulates lysosomal lipid metabolism during cold exposure in mice

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ACS Fall 2022

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