Loss of function of T-box 3 in the liver protects against MASLD
Jacquelyn J. Maher
Jacquelyn J. Maher
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Commentary

Loss of function of T-box 3 in the liver protects against MASLD

Abstract

The hallmark feature of metabolic dysfunction-associated steatotic liver disease (MASLD) is hepatic lipid accumulation. A recent search for genes impacting MASLD in mice uncovered the transcriptional repressor T-box 3 (Tbx3) as a top hit. In this issue of the JCI, Mannino et al. investigated the mechanism of action of TBX3 in murine MASLD. Tbx3 deletion protected against MASLD by inducing high density lipoprotein binding protein and stimulating hepatic VLDL secretion. Loss-of-function mutations in human TBX3 identified in MASLD patients displayed a similar protective effect. Collectively, these findings highlight the importance of lipid export in the prevention of MASLD and identify a transcriptional pathway controlling hepatic lipid secretion that is poised for further investigation.

Authors

Jacquelyn J. Maher

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Figure 1

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(A) Mice engineered to overexpress TBX3 in the liver developed MASLD in ...
(A) Mice engineered to overexpress TBX3 in the liver developed MASLD in response to WD. By contrast, genetic deletion of TBX3 from the liver (TBX3 knockout) protected mice from diet-induced MASLD. The protection from MASLD seen in TBX3-knockout mice coincided with increased VLDL secretion. TBX3 knockout resulted in upregulation of HDLBP (not shown); when HDLBP was also deleted (TBX3 + HDLBP knockout), the protective effect of TBX3 knockout was eliminated coincident with lower VLDL secretion. (B) Two point mutations in TBX3 (I155S and A280S) that localize to the DNA binding domain and presumably suppress transcriptional activity were identified in MASLD patients. When these mutations were expressed in mouse liver followed by WD feeding, they behaved similarly to TBX3 knockout in mice, protecting against diet-induced MASLD and enhancing VLDL secretion.