Somatic mutations in TBX3 promote hepatic clonal expansion by accelerating VLDL secretion
Open accessAbstract
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.
AI snapshot
Written from the paper’s full text.
TL;DR
Somatic TBX3 mutations are found in human fatty liver disease and act as loss-of-function alleles that expand hepatocyte clones by accelerating VLDL secretion. In mice, Tbx3 loss protects against Western diet–induced MASLD while causing hyperlipidemia and insulin resistance, illustrating a clone/organ benefit at organismal cost.
Key findings
- Human MASLD and alcohol-related liver disease livers contained somatic TBX3 mutations, several within the T-box DNA-binding domain; L207P, L263P, and I155S were predicted destabilizing (ΔΔG ≤ –2.0 kcal/mol), while A280S was modestly destabilizing (ΔΔG = –0.94 kcal/mol) near the DNA/protein interface.
- Hepatocyte-specific Tbx3 knockout protected WD-fed mice against MASLD: lower liver/body weight ratios, liver triglycerides, liver cholesterol, and NAFLD activity score after 6 months, plus decreased surface tumor numbers and sizes after 48 weeks; Tbx3 overexpression exacerbated WD-induced MASLD with increased liver weight, liver triglycerides, and plasma ALT/AST.
- Tbx3 loss accelerated VLDL-TG secretion and increased plasma ApoB and VLDL-fraction triglycerides; a choline-deficient diet abrogated protection. TBX3 bound 1,518 genes within 10 kb of their TSS, including Mttp and Chka; 47 bound genes were upregulated in KO livers, and Hdlbp was a direct target whose loss abrogated the increased VLDL-TG secretion in Tbx3/Hdlbp double-knockout livers.
- Human TBX3 I155S and A280S mutants failed to suppress VLDL secretion in vivo; I155S showed lower protein levels, and both I155S and A280S showed nuclear plus cytoplasmic localization, unlike WT, G35C, and F40L.
Methods
- Human liver sequencing data from MASLD and alcohol-related liver disease patients were analyzed; TBX3 mutations were mapped onto AlphaFold and PDB 1H6F structures, with stability effects predicted by DDMut.
- Mouse studies used liver-specific Tbx3 knockout via AAV8-TBG-Cre in Tbx3fl/fl mice, AAV8-TBG-V5-TBX3 overexpression, WD and CDA-HFD feeding, 48-week MASLD tumorigenesis, in vivo poloxamer-407 VLDL-TG secretion assays, ApoB ELISA, lipoprotein fractionation, GTT/insulin measurements, histology, qPCR, Western blotting, and immunofluorescence.
- Mechanistic work included MOSAICS CRISPR screening, CUT&RUN and ChIP-Seq, RNA-seq and Gene Ontology enrichment, H2.35 and HEK293T cell lines, Gaussia luciferase secretion assays, siRNA knockdown, lentiviral Tbx3 knockout/overexpression, and [13C]palmitate metabolomics/lipidomics; statistics used two-tailed unpaired Student’s t tests unless otherwise indicated.
Limitations
- The paper does not include a formal limitations section. In the Discussion, the authors state that TBX3 inhibition is likely not a viable treatment due to potential side effects; Tbx3-KO mice had increased systemic insulin resistance and hyperlipidemia, and elevated VLDL/LDL particles are known to cause atherosclerosis and cardiovascular disease. They also state that inter-organ trade-offs of somatic mutations must be quantified in vivo before therapeutic conclusions.
- Evident from the text: most mechanistic evidence comes from mouse models and cell lines, while human evidence is sequencing association plus functional testing of selected TBX3 mutants rather than direct demonstration of human clonal expansion causality.
- Evident from the text: for experiments other than the mouse MASLD phenotype, male mice were used because they generally develop more rapid and severe fatty liver disease, which may limit generalizability across sexes.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
8 of 9 cited sources checked · 4 supported · 0 flagged · accuracy not yet measured
- Premisecitation
In rats, pharmacologic inhibition of cholesterol synthesis causes developmental abnormalities.
“In rats, pharmacologic inhibition of cholesterol synthesis causes developmental abnormalities (34).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [34] source
- Premisecitation
Some mutations found in cirrhotic livers induce liver regeneration without promoting cancer.
“Importantly, some of these mutations induce liver regeneration without promoting cancer (31, 32).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [31] source
The Introduction reports that recurrently mutated genes with large effects on liver regeneration are not frequently detected in liver cancer. But it says they ‘do not appear to promote carcinogenesis,’ and the Discussion calls regeneration without transformation ‘likely’; the claim presents that uncertain conclusion as established. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [32] source
- Findingown data
TBX3 somatic mutations are detected in patients with MASLD.
“Here, we detected TBX3 somatic mutations in patients with metabolic dysfunction–associated steatotic liver disease (MASLD).”
Quote in the paperSubstantial claim - Findingown data
Choline-deficient diets abrogate the protective effect of Tbx3 deletion.
“Choline-deficient diets, which block VLDL secretion, abrogated this protective effect.”
Quote in the paperSubstantial claim - Findingown data
Tbx3-KO mice had an increased rate of VLDL-TG secretion.
“KO mice had an increased rate of VLDL-TG secretion (Figure 5, J and K).”
Quote in the paperSubstantial claim
- Findingown data
Tbx3 deletion protects against MASLD in mice.
“In mice, Tbx3 deletion protected against, whereas Tbx3 overexpression exacerbated, MASLD.”
Quote in the paperSubstantial claim - Findingown data
Hdlbp is a direct target of TBX3 responsible for altered VLDL secretion.
“Hdlbp is a direct target of TBX3 that is responsible for the altered VLDL secretion.”
Quote in the paperSubstantial claim - Findingown data
TBX3 binds to sites within 250 bp of Hdlbp's promoter in vitro and in vivo.
“In vitro and in vivo, TBX3 binds to sites within 250 bp of Hdlbp’s promoter (Figure 6G).”
Quote in the paperSubstantial claim - Findingown data
TBX3 I155S and A280S mutations found in patients fail to suppress VLDL secretion.
“In contrast to wild-type TBX3, the TBX3 I155S and A280S mutations found in patients failed to suppress VLDL secretion.”
Quote in the paperSubstantial claim - Findingown data
Loss of Hdlbp abrogated the increases in VLDL-TG secretion caused by loss of Tbx3.
“This showed that loss of Hdlbp abrogated the increases in VLDL-TG secretion caused by loss of Tbx3 (Figure 6K).”
Quote in the paperSubstantial claim - Findingown data
Tbx3 overexpression exacerbates MASLD in mice.
“In mice, Tbx3 deletion protected against, whereas Tbx3 overexpression exacerbated, MASLD.”
Quote in the paperSubstantial claim - Findingown data
Tbx3 deletion reduces lipid overload by accelerating VLDL secretion.
“Tbx3 deletion reduced lipid overload by accelerating VLDL secretion.”
Quote in the paperSubstantial claim - Findingown data
Mutations in TBX3 provide a selective advantage in MASLD at the cellular level by accelerating the rate of VLDL-TG secretion.
“Here, we show that mutations in TBX3 provide a selective advantage in MASLD at the cellular level by accelerating the rate of VLDL-TG secretion.”
Quote in the paperSubstantial claim - Interpretationown data
Tbx3 loss confers a selective advantage to hepatocyte clones during MASLD development.
“suggesting that Tbx3 loss confers a selective advantage to hepatocyte clones during MASLD development.”
Quote in the paperSubstantial claim - Interpretationown data
Hdlbp is a key downstream target of TBX3 that mediates the enhanced secretion of VLDL particles.
“These results demonstrated that Hdlbp is a key downstream target of TBX3 that mediates the enhanced secretion of VLDL particles.”
Quote in the paperSubstantial claim - Interpretationown data
TBX3 directly suppresses the cholesterol biosynthetic pathway.
“further showing that TBX3 directly suppresses the cholesterol biosynthetic pathway.”
Quote in the paperSubstantial claim - Interpretationreasoning
This role in cholesterol homeostasis plays a role in TBX3's suppression of VLDL secretion.
“These results suggest that TBX3 assists in maintaining cholesterol homeostasis, which plays a role in its suppression of VLDL secretion and may also be important for its role in embryogenesis.”
Quote in the paperSubstantial claim - Interpretationreasoning
TBX3 assists in maintaining cholesterol homeostasis.
“These results suggest that TBX3 assists in maintaining cholesterol homeostasis, which plays a role in its suppression of VLDL secretion and may also be important for its role in embryogenesis.”
Quote in the paperNot a substantial claim - Interpretationreasoning
These results call into question the idea that somatic mutations are predominantly harmful.
“These results call into question the idea that somatic mutations are predominantly harmful.”
Quote in the paperSubstantial claim- Rests on an assumption: Several mutations found in cirrhotic livers are not commonly found in hepatocellular carcinoma.
- Interpretationown data
Secreting lipids, rather than storing them, is a general mechanism that drives expansion of hepatocyte clones during MASLD development, including TBX3 mutant clones.
“We further provide evidence that secreting lipids, rather than storing them, is a general mechanism that drives expansion of hepatocyte clones during MASLD development, including TBX3 mutant clones.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 4
- May combine two claims. 12
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn the esophagus, clonally expanding epithelial cells restrict tumorigenesis by outcompeting emerging cancer cells.
“In the esophagus, clonally expanding epithelial cells restrict tumorigenesis by outcompeting emerging cancer cells (29, 30).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [29] source
The Discussion (page not provided) says Notch1-mutant clones expand in normal esophageal epithelium by driving neighboring wild-type cells to differentiate. The paper also reports that Notch1 loss slows tumor growth, but it does not show that expanding epithelial clones restrict tumorigenesis by outcompeting emerging cancer cells. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [30] source
The Abstract and ‘Epithelial mutant clones displace tumors’ section report that expanding mutant clones in normal mouse esophageal epithelium eliminate early tumors through competition. The claim omits the mouse-model qualification and calls the emerging, pre-malignant tumor cells ‘cancer cells’; the Discussion says whether the mechanism occurs in humans is unknown. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHigh-dose triglyceride infusion is a common method of inducing acute insulin resistance in mice and humans.
“High-dose triglyceride infusion is a common method of inducing acute insulin resistance in mice and humans (37), so it is possible that chronic hyperlipidemia resulting from accelerated VLDL secretion exacerbated the insulin resistance phenotype caused by the WD.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [37] source
In “Testing Randle and colleagues’ hypothesis” (page unavailable), the paper reports that lipid infusions induced insulin resistance in healthy people within about three hours. “Other hypotheses” (page unavailable) mentions rodents developing insulin resistance after acute lipid infusion, but does not specify mice. The copy does not establish that high-dose triglyceride infusion, specifically, is a common method in both mice and humans. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTM6SF2 regulates the number of triglycerides per VLDL particle without influencing the number of VLDL particles secreted.
“This differs from other genes implicated in VLDL particle formation and MASLD, such as TM6SF2, which regulates the number of triglycerides per VLDL particle without influencing the number of VLDL particles secreted (33).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [33] source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationElevated levels of VLDL and LDL particles are known to cause atherosclerosis and cardiovascular disease.
“Furthermore, elevated levels of VLDL and LDL particles are known to cause atherosclerosis and cardiovascular disease (38).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [38] source
May combine two claims.
Findingown dataWT TBX3 suppressed VLDL secretion, while I155S and A280S point mutants showed a complete inability to do so.
“While WT TBX3 suppressed VLDL secretion, I155S and A280S point mutants showed a complete inability to do so (Figure 7, E and F).”
Quote in the paperSubstantial claimMay combine two claims.
Findingnone givenTBX3 transcriptionally suppresses the conventional secretory pathway and cholesterol biosynthesis.
“TBX3 transcriptionally suppressed the conventional secretory pathway and cholesterol biosynthesis.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAfter 6 months WD, Tbx3-KO mice had lower liver/body weight ratios, liver triglycerides, and liver cholesterol.
“Again, Tbx3-KO mice had lower liver/body weight ratios, liver triglycerides, and liver cholesterol (Figure 2, G–I).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOn WD, Tbx3 overexpression led to increases in liver weight, body weight, liver/body weight ratios, and liver triglycerides after 3 months.
“On WD, Tbx3 overexpression led to increases in liver weight, body weight, liver/body weight ratios, and liver triglycerides after 3 months (Figure 3, G and H).”
Quote in the paperSubstantial claimMay combine two claims.
FindingreasoningDespite being protected from MASLD, Tbx3-KO mice faced other health challenges, such as increased systemic insulin resistance.
“Despite being protected from MASLD, Tbx3-KO mice faced other health challenges, such as increased systemic insulin resistance.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTBX3 mutations increase the rate of VLDL particle secretion, resulting in an elevated VLDL particle number.
“Notably, TBX3 mutations increase the rate of VLDL particle secretion, resulting in an elevated VLDL particle number.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataTBX3 somatic mutations identified in human patients are predominantly loss-of-function and likely promote MASLD-driven clonal expansion through accelerated VLDL particle secretion.
“This showed that TBX3 somatic mutations identified in human patients are predominantly loss-of-function, and likely promote MASLD-driven clonal expansion through accelerated VLDL particle secretion.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataTBX3 mutant clones expand during MASLD through increased lipid disposal, and clonal fitness can benefit the liver at the cost of hyperlipidemia.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataCDA-HFD impairs the central mechanism of Tbx3 loss, accelerated VLDL particle secretion, thereby ablating protective phenotypes associated with Tbx3 deletion.
“These results demonstrated that CDA-HFD impairs the central mechanism of Tbx3 loss, namely accelerated VLDL particle secretion, thereby ablating the protective phenotypes associated with Tbx3 deletion.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationIn humans, inborn errors of cholesterol synthesis induce different malformation syndromes, many of which present clinically with underdeveloped limbs, mirroring features of ulnar mammary syndrome caused by germline TBX3 mutations.
“In humans, inborn errors of cholesterol synthesis induce different malformation syndromes (35), many of which present clinically with underdeveloped limbs, mirroring features of ulnar mammary syndrome caused by germline TBX3 mutations.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] source
May combine two claims.
InterpretationreasoningSomatic mutations can have potent beneficial effects at the clone, tissue, and organ levels, but also a detrimental effect on the individual.
“This study is important because it shows that somatic mutations can have potent beneficial effects at the clone, tissue, and organ levels, but also a detrimental effect on the individual.”
Quote in the paperSubstantial claim
The paper relies on this without support.
No link had been made between TBX3 and chronic liver disease.
“However, no link has been made between TBX3 and chronic liver disease.”
The paper relies on this without support.
Several mutations found in cirrhotic livers are not commonly found in hepatocellular carcinoma.
“In the liver, several mutations found in cirrhotic livers are not commonly found in hepatocellular carcinoma.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Mannino and colleagues identified TBX3 mutations in four MASLD subjects, some of which localized to the DNA binding domain.
“They identified TBX3 mutations in four MASLD subjects, some of which localized to the DNA binding domain.”
From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [4]
The Results section, “Somatic mutations in TBX3 are observed in human livers” (page unavailable), reports TBX3 mutations in liver tissues from patients with MASLD and alcohol-related liver disease, several within the T-box DNA-binding domain. It does not state that mutations were found in four MASLD subjects, so the subject count is unsupported by our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe mutant TBX3 proteins enabled secretion of a model compound better than wild-type TBX3 in H2.35 murine hepatocytes.
“To test this hypothesis, the authors expressed the mutant proteins in H2.35 murine hepatocytes and demonstrated that they enabled secretion of a model compound better than wild-type TBX3.”
From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [4]
The Results section (“Human TBX3 point mutations result in loss of functionality”) reports that DNA-binding-domain mutants, particularly I155S, suppressed Gaussia luciferase secretion less than wild-type TBX3 in H2.35 cells. But mutations upstream of the DNA-binding domain behaved similarly to wild type, so the finding does not apply to all the mutant proteins tested. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThis exacerbation of diet-induced MASLD did not coincide with any change in insulin sensitivity.
“This exacerbation of diet-induced MASLD did not coincide with any change in insulin sensitivity.”
From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [4]
The Results section, “Tbx3 overexpression exacerbates WD-induced MASLD development” (page not provided), reports that Tbx3 overexpression worsened Western-diet-induced MASLD. It does not report insulin-sensitivity measurements for those mice. A separate Results section reports increased insulin resistance in Tbx3-knockout mice, which cannot establish unchanged insulin sensitivity in the overexpression experiment. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe reduction in hepatic steatosis was most pronounced, with a lesser reduction in liver injury as measured by plasma alanine aminotransferase.
“Most pronounced was a reduction in hepatic steatosis, with a lesser reduction in liver injury as measured by plasma alanine aminotransferase.”
From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [4]
In Results, ‘Tbx3 loss protects against MASLD development’ (page unavailable), the paper reports reduced steatosis and plasma ALT after three months of a Western diet. After six months, steatosis-related measures remained lower, but plasma ALT was similar in knockout and control mice. Thus, the claim captures the stronger steatosis effect but does not qualify the ALT reduction by time point. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDespite its beneficial effect on hepatic steatosis, Tbx3 deletion promotes insulin resistance and hypertriglyceridemia in mice.
“The reason is that despite its beneficial effect on hepatic steatosis, Tbx3 deletion promotes insulin resistance and hypertriglyceridemia in mice.”
From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [4]
The Results section, “Tbx3 loss does not improve fatty liver through altered insulin resistance” (page not available), reports increased triglycerides and indicators of insulin resistance in Tbx3-KO mice studied for fatty liver disease. It also states that mice on a normal diet had elevated triglycerides but similar glucose tolerance and fasting insulin to controls; Tbx3 loss alone was insufficient to drive insulin resistance. The claim omits that diet-dependent qualification. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Loss-of-function mutations in human TBX3 identified in MASLD patients displayed a similar protective effect.
“Loss-of-function mutations in human TBX3 identified in MASLD patients displayed a similar protective effect.”
From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [4]
Tbx3 deletion protected against MASLD by inducing high density lipoprotein binding protein and stimulating hepatic VLDL secretion.
“Tbx3 deletion protected against MASLD by inducing high density lipoprotein binding protein and stimulating hepatic VLDL secretion.”
From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [4]
Tbx3 deletion induces Hdlbp expression.
“After verifying that Tbx3 deletion induces Hdlbp expression, the authors demonstrated that deleting Hdlbp in a Tbx3-deficient liver was sufficient to eliminate the beneficial effect of Tbx3 deletion on hepatic lipid secretion (Figure 1A).”
From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [4]
Mice with mutant TBX3 developed less hepatic lipid accumulation than those with wild-type TBX3, similar to the effect seen in Tbx3-deficient mice.
“Moreover, mice with mutant TBX3 developed less hepatic lipid accumulation than those with wild-type TBX3, similar to the effect seen in Tbx3-deficient mice (Figure 1B).”
From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [4]
Loss of Tbx3 led to an induction of several genes involved in hepatic lipid secretion, and specifically genes regulating the synthesis of lipids and proteins involved in VLDL assembly.
“Investigating how liver-specific Tbx3 deletion could result in an improvement in hepatic lipid homeostasis during a WD challenge, the authors found that loss of Tbx3 led to an induction of several genes involved in hepatic lipid secretion, and specifically genes regulating the synthesis of lipids and proteins involved in VLDL assembly.”
From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [4]
Liver-specific Tbx3 deletion stimulated hepatic VLDL secretion, resulting in elevations of plasma triglyceride and apolipoprotein B (ApoB).
“In accord with this observation, the authors showed that liver-specific Tbx3 deletion stimulated hepatic VLDL secretion, resulting in elevations of plasma triglyceride and apolipoprotein B (ApoB) (Figure 1A).”
From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [4]
Mannino and colleagues found a similar biphasic change in mouse liver in response to a 36-week Western diet.
“Reviewing transcriptional data from a human database, they reported an increase in TBX3 expression in early MASLD followed by a decline as the disease progresses; they found a similar biphasic change in mouse liver in response to a 36-week WD.”
From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [4]
AAV-mediated overexpression of Tbx3 in mouse liver followed by 3 months of Western diet prompted an increase in hepatic lipids as well as an increase in plasma transaminases.
“Conversely, AAV-mediated overexpression of Tbx3 in mouse liver followed by 3 months of WD prompted an increase in hepatic lipids as well as an increase in plasma transaminases.”
From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [4]
Two specific mutations in the DNA binding region (I155S and A280S) interfered with the nuclear localization of TBX3, and thus presumably inhibited its transcriptional activity.
“Two specific mutations in the DNA binding region (I155S and A280S) interfered with the nuclear localization of TBX3, and thus presumably inhibited its transcriptional activity.”
From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [4]
Deleting Hdlbp in a Tbx3-deficient liver was sufficient to eliminate the beneficial effect of Tbx3 deletion on hepatic lipid secretion.
“After verifying that Tbx3 deletion induces Hdlbp expression, the authors demonstrated that deleting Hdlbp in a Tbx3-deficient liver was sufficient to eliminate the beneficial effect of Tbx3 deletion on hepatic lipid secretion (Figure 1A).”
From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [4]
Overexpression of the two TBX3 mutants in mouse liver in vivo preserved triglyceride secretion after Western diet feeding, where it was suppressed in mice with wild-type TBX3.
“They then overexpressed the two TBX3 mutants in mouse liver in vivo, and demonstrated that triglyceride secretion was preserved after WD feeding, where it was suppressed in mice with wild-type TBX3.”
From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [4]
The beneficial effect of Tbx3 deficiency seen with Western diet-induced MASLD was nearly completely abrogated in CDAHFD-induced MASLD.
“Indeed, the beneficial effect of Tbx3 deficiency seen with WD-induced MASLD was nearly completely abrogated in CDAHFD-induced MASLD.”
From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [4]
Reviewing transcriptional data from a human database, Mannino and colleagues reported an increase in TBX3 expression in early MASLD followed by a decline as the disease progresses.
“Reviewing transcriptional data from a human database, they reported an increase in TBX3 expression in early MASLD followed by a decline as the disease progresses; they found a similar biphasic change in mouse liver in response to a 36-week WD.”
From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [4]
The Results section, “Tbx3 loss protects against MASLD development” (page unavailable), reports an early rise and later decline in liver Tbx3 expression in Western-diet-fed mice. I found no passage reporting that pattern in human transcriptional data or describing an analysis of a human database; the human-patient passages concern TBX3 mutations instead. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Somatic Mutations Increase Hepatic Clonal Fitness and Regeneration in Chronic Liver Disease
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Self-citationMutant clones in normal epithelium outcompete and eliminate emerging tumours
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“Genomic sequencing of liver tissues from MASLD and alcohol-related liver disease patients identified somatic mutations in TBX3 (10), several of which fell within the T-box DNA-binding domain (Figure 1C), indicating that TBX3 mutations may also promote clonal expansion in human disease.”
Self-citationA body map of somatic mutagenesis in morphologically normal human tissues
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“Tbx3 -null embryos die in utero (12–14), highlighting its importance during embryonic development.”
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Self-citationMetabolic inflexibility promotes mitochondrial health during liver regeneration
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Self-citationThe RNA-binding protein vigilin regulates VLDL secretion through modulation of Apob mRNA translation
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“Within the liver, Tbx3 is expressed in zone 3 hepatocytes, downstream of canonical Wnt signaling (16).”
PKD1 mutant clones within cirrhotic livers inhibit steatohepatitis without promoting cancer
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Self-citation
Flagged first, then by citations
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Loss of function of T-box 3 in the liver protects against MASLD
Maher, J. J. (2025) · Journal of Clinical Investigation · doi:10.1172/jci197143
- Authors
- Mannino, G., Quinn, G., Zhu, M., Wang, Z., Wang, X., Li, B., Hsieh, M.-H., Mathews, T., Zacharias, L., Gu, W., Gopal, P., Brzozowska, N., Campbell, P., Hoare, M., Liszczak, G., & Zhu, H.
- Affiliations
- Harold C. Simmons Comprehensive Cancer Center
- The University of Texas Southwestern Medical Center (US)
- Wellcome Sanger Institute (GB)
- University of Cambridge Department of Medicine, Cambridge Biomedical Campus, Cambridge, United Kingdom.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2025-07-10
- Volume
- 135
- Issue
- 18
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC12435840
- OpenAlex
- W4412163146
- Semantic Scholar
- 6fbcce737c195b8bc1db617f77bb3c13bb3e8d74
- Cited by
- 4
- References
- 39
- Citations by year
- 2026: 3 · 2025: 1
- FWCI
- 2.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Clinical Investigation (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- PubMed Central (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Funders
- Alnylam Pharmaceuticals
- University of Texas Southwestern Medical Center
- National Institutes of Health (5t32ai005284-45, 5p30dk127984-04)
- Nutrition Obesity Research Center, University of North Carolina
- National Cancer Institute (R01CA251928, P30CA142543)
- National Institute of Allergy and Infectious Diseases (T32-AI005284)
- National Institute of Diabetes and Digestive and Kidney Diseases (DP1 DK139976)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- TBX3, somatic mutations, clonal expansion, hepatocytes, non-alcoholic fatty liver disease, VLDL secretion, lipid overload, choline deficiency, cholesterol biosynthesis, secretory pathway, hyperlipidemia, hepatic steatosis, clonal fitness
- MeSH terms
- Animals, Fatty Liver, Female, Humans, Lipoproteins, VLDL, Liver, Male, Mutation, Mice, Knockout, Mutation, Missense, T-Box Domain Proteins, Hepatocytes, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-22.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-22.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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