Somatic mutations in TBX3 promote hepatic clonal expansion by accelerating VLDL secretion
Gregory Mannino, Gabriella Quinn, Min Zhu, Zixi Wang, Xun Wang, Boyuan Li, Meng-Hsiung Hsieh, Thomas Mathews, Lauren Zacharias, Wen Gu, Purva Gopal, Natalia Brzozowska, Peter Campbell, Matt Hoare, Glen Liszczak, Hao Zhu
Gregory Mannino, Gabriella Quinn, Min Zhu, Zixi Wang, Xun Wang, Boyuan Li, Meng-Hsiung Hsieh, Thomas Mathews, Lauren Zacharias, Wen Gu, Purva Gopal, Natalia Brzozowska, Peter Campbell, Matt Hoare, Glen Liszczak, Hao Zhu
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Research Article Cell biology Gastroenterology

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

Abstract

Somatic mutations that increase clone fitness or resist disease are positively selected, but the impact of these mutations on organismal health remains unclear. We previously showed that Tbx3 deletion increases hepatocyte fitness within fatty livers. Here, we detected TBX3 somatic mutations in patients with metabolic dysfunction–associated steatotic liver disease (MASLD). In mice, Tbx3 deletion protected against, whereas Tbx3 overexpression exacerbated, MASLD. Tbx3 deletion reduced lipid overload by accelerating VLDL secretion. Choline-deficient diets, which block VLDL secretion, abrogated this protective effect. TBX3 transcriptionally suppressed the conventional secretory pathway and cholesterol biosynthesis. Hdlbp is a direct target of TBX3 that is responsible for the altered VLDL secretion. In contrast to wild-type TBX3, the TBX3 I155S and A280S mutations found in patients failed to suppress VLDL secretion. In conclusion, TBX3 mutant clones expand during MASLD through increased lipid disposal, demonstrating that clonal fitness can benefit the liver at the cost of hyperlipidemia.

Authors

Gregory Mannino, Gabriella Quinn, Min Zhu, Zixi Wang, Xun Wang, Boyuan Li, Meng-Hsiung Hsieh, Thomas Mathews, Lauren Zacharias, Wen Gu, Purva Gopal, Natalia Brzozowska, Peter Campbell, Matt Hoare, Glen Liszczak, Hao Zhu

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Figure 5

Tbx3 deletion protects against MASLD by transcriptionally upregulating VLDL-TG particle secretion.

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Tbx3 deletion protects against MASLD by transcriptionally upregulating ...
(A) qPCR results for genes involved in de novo lipogenesis from Tbx3-KO or -WT mice fed a WD for 6 months. (B) qPCR for free fatty acid uptake genes in mice from A. (C) qPCR for β-oxidation genes in mice from A. (D) qPCR for PC biosynthesis and VLDL secretion genes in mice from A. (E) qPCR for PC biosynthesis and VLDL secretion genes in Tbx3-WT or -KO mice fed a WD for 4 weeks. (F) qPCR for β-oxidation genes in mice from E. (G) Ratio of M+14 myristoylcarnitine to M+16 palmitoylcarnitine in the liver of Tbx3-KO or -WT mice fed a WD for 2 weeks. (H) Lipoprotein fractionation (left) and total plasma triglyceride concentration (right) from Tbx3-KO mice fed a WD for 4 weeks. For lipoprotein fractionation, plasma was pooled from 4 mice per group. (I) Experimental setup for in vivo VLDL triglyceride secretion assay. (J) Plasma triglyceride levels over time from Tbx3-KO or -WT mice fed a WD for 2 weeks. Tbx3 KO, n = 8; Tbx3 WT, n = 7. (K) Quantification of the triglyceride secretion rate from mice from K. (L) Plasma concentration of total apolipoprotein B (ApoB) 3 hours after poloxamer injection in mice from K. (M) Experimental setup to induce MASLD with a CDA-HFD. (N) Liver weight (left), body weight (middle), and liver/body weight ratio (right) of Tbx3-KO or -WT mice fed a CDA-HFD for 14 weeks. (O) Representative H&E images in mice from N. 61. Significance of the difference in plasma triglycerides at 180 minutes after P407 injection in J was calculated using a 2-way ANOVA with Šidák’s post hoc test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Scale bars: 500 μm, left panels; 100 μm, right panels.