Somatic mutations in TBX3 promote hepatic clonal expansion by accelerating VLDL secretion

We’ve previously demonstrated that hepatocytes with Tbx3 deletions have increased cellular fitness and clonally expand during metabolic-dysfunction associated steatotic liver disease (MASLD) development. TBX3 is a transcription factor that is critical for embryonic development, but has never been studied within the context of MASLD. Here, we show that somatic mutations in TBX3 are found in human patients with MASLD. Liver specific deletion of Tbx3 in mice protects against diet induced MASLD through upregulating VLDL-TG particle secretion. TBX3 transcriptionally suppresses the conventional secretory pathway and cholesterol biosynthesis. Hdlbp is a direct target of TBX3 that is responsible for altered VLDL secretion. In contrast to WT TBX3, TBX3 harboring somatic mutations found in humans failed to suppress VLDL secretion in vivo. In conclusion, mutations in TBX3 promote clonal expansion during MASLD development through increased lipid disposal, demonstrating clonal fitness can benefit the liver even at the cost of hyperlipidemia.