Selective mTOR inhibition via FLCN drives TFE3-dependent VLDL-TG secretion and protects from MAFLD/MASH

ABSTRACT: Hepatic lipid homeostasis is controlled by multiple processes, including VLDL-TG secretion. We have previously shown that the FLCN/TFE3 branch of mTORC1 signaling controls hepatic fatty acid oxidation and de novo lipogenesis to protect mice from MAFLD. We now show that the FLCN/TFE3 pathway also controls VLDL-TG secretion via direct transcriptional activation of a broad program of genes involved in VLDL-TG secretion, including PCYT1A, the rate-limiting step of phosphatidylcholine synthesis. Loss of hepatic FLCN upregulates VLDL-TG secretion and prevents MAFLD, and this protection requires TFE3 and PCYT1A. The data unveil a new pathway that orchestrates multiple steps of VLDL-TG synthesis and secretion. The data also highlight that suppressing the selective FLCN/TFE3 branch of mTORC1 signaling maximizes hepatic lipid clearance by coordinately promoting fatty acid oxidation, suppressing de novo lipogenesis, and boosting VLDL-TG secretion, providing an attractive therapeutic target for the treatment of MAFLD.

INSTRUMENT(S): Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS15598 | MetaboLights | 2026-09-08

REPOSITORIES: MetaboLights