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 3

Overexpression of Tbx3 exacerbates MASLD.

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Overexpression of Tbx3 exacerbates MASLD. (A) Representative V5 staining...
(A) Representative V5 staining from WT mice injected with AAV8-TBG-V5-GFP or AAV8-TBG-V5-TBX3. (B) Tbx3 mRNA levels from livers of mice overexpressing GFP or TBX3. (C)Liver/body weight ratio of Tbx3-overexpressing mice on NC for 3 months. (D) Plasma ALT from mice in C. (E) Plasma AST from mice in C. (F) Representative H&E images from mice in C. (G) Liver weight (left), body weight (middle), and liver/body weight ratio (right) of Tbx3-overexpressing mice on WD for 3 months. (H) Liver triglyceride measurements from mice in G. (I) Representative H&E images from mice in G. (J) Plasma ALT from mice in G. One outlier from each group was excluded. (K) Plasma AST from mice in G. One outlier from each group was excluded. (L) Experimental schema to test the fitness of Tbx3-expressing hepatocytes during WD feeding. (M) Representative V5 staining from WT mice injected with AAV8-TBG-V5-GFP or AAV8-TBG-V5-TBX3 after 4 weeks of NC or WD. (N) Quantification of relative abundance of V5-expressing cells from H. Significance of the V5+ quantification in N was calculated using a 2-way ANOVA with Tukey’s post hoc test. *P < 0.05; **P < 0.01; ***P < 0.001. Scale bars: 500 μm, left panels; 100 μm, right panels.