CoChat
Sign Up
Cited by 0Liver Disease Diagnosis and TreatmentLipid metabolism and disordersCholesterol and Lipid Metabolism

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

Open access
Maher, Jacquelyn J.·2025·Journal of Clinical Investigation
DOI 10.1172/jci197143PMC PMC12435830
Open this paper in CoChat — free accountOpen PDF

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.

AI snapshot

Written from the paper’s full text.

TL;DR

This JCI commentary reviews Mannino et al.'s work showing that loss of function of the transcriptional repressor T-box 3 (TBX3) protects against metabolic dysfunction-associated steatotic liver disease (MASLD) in mice by inducing high density lipoprotein binding protein (HDLBP) and stimulating hepatic VLDL secretion. Human TBX3 loss-of-function variants identified in MASLD patients produced a similar protective effect, though TBX3 suppression is not considered a viable therapy because Tbx3 deletion promotes insulin resistance and hypertriglyceridemia.

Key findings

  • MOSAICS screening in Cas9-expressing mice on a MASLD-promoting Western diet (WD) for 6 months identified TBX3 as a regulator of hepatic steatosis; AAV-mediated liver-specific Tbx3 deletion reduced MASLD features after WD feeding, most pronounced for hepatic steatosis with lesser reduction in plasma alanine aminotransferase.
  • Conversely, AAV-mediated Tbx3 overexpression followed by 3 months of WD increased hepatic lipids and plasma transaminases without changing insulin sensitivity.
  • Tbx3 deletion induced genes involved in hepatic lipid secretion and VLDL assembly, stimulating VLDL secretion and elevating plasma triglyceride and apolipoprotein B (ApoB); the protective effect was nearly completely abrogated when mice were fed a choline-deficient, amino acid-supplemented high-fat diet (CDAHFD).
  • TBX3 mutations were identified in four MASLD subjects; two DNA-binding-domain mutations (I155S and A280S) interfered with nuclear localization, and when overexpressed in mouse liver preserved triglyceride secretion after WD feeding and produced less hepatic lipid accumulation than wild-type TBX3.
  • Deleting Hdlbp in a Tbx3-deficient liver eliminated the beneficial effect of Tbx3 deletion on hepatic lipid secretion, validating a TBX3–HDLBP–VLDL secretion axis.
  • The commentary notes that roughly 50% of persons with MASLD exhibit a phenotype characteristic of reduced VLDL secretion.

Methods

  • This is a commentary/editorial article summarizing the primary study by Mannino et al. (J Clin Invest 2025;135:e191855); it does not report original experiments.
  • It describes the primary study's design: MOSAICS (method of somatic AAV-transposon in vivo clonal screening) in mouse liver, liver-specific Tbx3 deletion and overexpression in mice fed WD or CDAHFD, transcriptional target analysis comparing TBX3-bound genes with genes upregulated in WD-fed Tbx3-knockout livers, and reverse-translation experiments expressing human TBX3 mutants in H2.35 murine hepatocytes and mouse liver.
  • Human data described include TBX3 mutations in four MASLD subjects and transcriptional database analysis showing a biphasic TBX3 expression pattern (increase in early MASLD, decline with progression), mirrored in mouse liver after 36-week WD.

Limitations

  • Stated in the paper: the authors have already considered but dismissed TBX3 suppression as a MASLD therapy because, despite its beneficial effect on hepatic steatosis, Tbx3 deletion promotes insulin resistance and hypertriglyceridemia in mice.
  • Stated in the paper: the authors selected Hdlbp for further exploration but did not elaborate on other relevant TBX3 targets, so Hdlbp may not be the sole target impacting hepatic lipid secretion.
  • Evident from the text: this is a commentary rather than primary research, so its findings are a summary and interpretation of Mannino et al.'s data rather than independently generated results.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1172/jci197143

Cites

18 of 18 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

41 of 43 cited sources checked · 23 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Placing mice on a MASLD-promoting Western diet for 6 months led to the clonal expansion of cells whose loss-of-function variants protected against disease.

    “Placing these mice on a MASLD-promoting Western diet (WD) for 6 months led to the clonal expansion of cells whose loss-of-function variants protected against disease (3).”
    Quote in the paperSubstantial claim1 of 1 sources checked
  • Premisecitation

    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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
  • Premisecitation

    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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [4] source

      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
  • Premisecitation

    In extended work, MOSAICS identified the transcription factor T-box 3 (TBX3) as a regulator of hepatic steatosis.

    “In this extended work, MOSAICS identified the transcription factor T-box 3 (TBX3) as a regulator of hepatic steatosis, which was noteworthy as TBX3 had not been previously linked to MASLD.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • Rests on an assumption: TBX3 had not been previously linked to MASLD.
  • Premisecitation

    A recent search for genes impacting MASLD in mice uncovered the transcriptional repressor T-box 3 (Tbx3) as a top hit.

    “A recent search for genes impacting MASLD in mice uncovered the transcriptional repressor T-box 3 (Tbx3) as a top hit.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [3] source

      The Results section, “Tbx3, Bcl6, and Smyd2 loss showed protection against fatty liver disease” (page unavailable), identifies Tbx3 among the strongest hits in mouse knockout tests of fatty liver disease. It calls TBX3 a T-box transcription factor, however, not a transcriptional repressor; the passage applies that description to Bcl6. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • May combine two claims. 16
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Premisecitation

    The disease-promoting variant of TM6SF2 (E167K) suppresses hepatic triglyceride secretion without affecting ApoB secretion, meaning that affected patients still secrete VLDL particles but with low lipid content.

    “although the disease-promoting variant of TM6SF2 (E167K) suppresses hepatic triglyceride secretion, it does so without affecting ApoB secretion, meaning that affected patients still secrete VLDL particles but with low lipid content (11–13).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [11] source

      The Results and Discussion report reduced VLDL triglyceride secretion without reduced apoB-100 secretion, consistent with smaller, lipid-poor particles—but these measurements were made in Tm6sf2 knockout mice. The Introduction identifies the human E167K variant as associated with fatty liver disease; this paper does not establish the claimed secretion pattern in patients carrying that variant. Page numbers were not provided in the passages. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [12] Reyes-Soffer G, et al. TM6SF2 determines both the degree of lipidation and the number of VLDL particles secreted by the liver [preprint]. https://doi.org/10.1101/2023.06.23.23291823 Posted on medRxiv June 29, 2023 source

      The Results (Lipoprotein APOB100 and lipid levels; page unavailable) report no difference in VLDL triglyceride production between variant carriers and their siblings, but significantly greater VLDL-APOB100 production in carriers. The Discussion likewise describes increased secretion of smaller, less-lipidated particles. Thus the smaller-particle conclusion is supported, but the claimed combination of suppressed triglyceride secretion and unaffected ApoB secretion is contrary to this paper’s human findings. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [13] source

      The section on TM6SF2 regulation reports reduced VLDL triglyceride secretion, and the Conclusion describes TM6SF2’s role in adding triglycerides to nascent, lipid-poor VLDL. But the Conclusion says APOB100 secretion has been reported as unchanged, reduced, or increased; the Human Studies section likewise reports reduced APOB production in one study and increased secretion in another. The claim that affected patients secrete VLDL without any change in ApoB secretion is therefore too categorical. Page numbers were not supplied for these passages. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The top hits from the prior MOSAICS study were all genes with known relevance to MASLD, which established the validity of the approach.

    “The top hits from this study were all genes with known relevance to MASLD, which established the validity of the approach.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [4] source

      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 measured

  • May combine two claims.

    Premiseown data

    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.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    The 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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [4] source

      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 measured

  • May combine two claims.

    Premiseown data

    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).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premiseown data

    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.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    GWAS have identified numerous variants that pose a risk for MASLD; these variants influence a number of metabolic processes such as intestinal lipid absorption, insulin sensitivity, hepatic lipogenesis and mitochondrial respiration.

    “To date, GWAS have identified numerous variants that pose a risk for MASLD; although these variants influence a number of metabolic processes such as intestinal lipid absorption, insulin sensitivity, hepatic lipogenesis and mitochondrial respiration (9, 10), the two variants with the highest significance in nearly all GWAS — PNPLA3 (patatin-like phospholipase domain-containing protein 3) and TM6SF”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [9] source

      The Discussion (page not provided) reports 77 loci associated with chronic ALT elevation as a proxy for NAFLD, with 17 SNP associations replicated against biopsy- or imaging-defined disease. It also links implicated genes to hepatic lipogenesis and broader metabolic pathways. The passages do not establish the claimed effects on intestinal lipid absorption, insulin sensitivity, or mitochondrial respiration. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [10] source

      The Discussion reports 17 NAFLD-associated loci and links implicated genes to intestinal lipid absorption, insulin signaling, and hepatic de novo lipogenesis. It also mentions mitochondrial processes, but does not establish that the identified variants influence mitochondrial respiration specifically. The paper uses the term NAFLD rather than MASLD; page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Despite 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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [4] source

      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

  • May combine two claims.

    Premiseown data

    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).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A single nucleotide polymorphism in transmembrane-6 superfamily member 2 (TM6SF2) is strongly associated with MASLD risk.

    “Noteworthy among these is a single nucleotide polymorphism in transmembrane-6 superfamily member 2 (TM6SF2), which is strongly associated with MASLD risk (7–10).”
    Quote in the paperNot a substantial claim4 of 4 sources checked

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    The work of Mannino and colleagues reveals a role for TBX3 not only in MASLD through regulation of Hdlbp and VLDL but also in the general control of cellular secretion.

    “Taken as a whole, the work of Mannino and colleagues stands out for its comprehensive analysis of TBX3, revealing a role for the transcription factor not only in MASLD through regulation of Hdlbp and VLDL but also in the general control of cellular secretion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The CDAHFD causes hepatic steatosis by limiting the chemical building blocks necessary for VLDL production, and thus should not be salvageable by genetic means.

    “The CDAHFD causes hepatic steatosis by limiting the chemical building blocks necessary for VLDL production (5, 6), and thus should not be salvageable by genetic means.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] source
    • cites [6] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    The reverse translation experiments with human TBX3 demonstrate its relevance to human liver disease.

    “In addition, the elegant reverse translation experiments with human TBX3 demonstrate its relevance to human liver disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    TBX3 deficiency prevents MASLD by stimulating the secretion of both triglyceride and ApoB, suggesting that it increases the number of VLDL particles released into the circulation.

    “TBX3 deficiency, by contrast, prevents MASLD by stimulating the secretion of both triglyceride and ApoB, suggesting that it increases the number of VLDL particles released into the circulation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    TBX3, unlike MTTP and TM6SF2, is a transcription factor, and thus has the potential to regulate more than one gene in the VLDL secretory pathway.

    “A second takeaway is that TBX3, unlike MTTP and TM6SF2, is a transcription factor, and thus has the potential to regulate more than one gene in the VLDL secretory pathway.”
    Quote in the paperNot a substantial claim
18 of 18

  • The paper relies on this without support.

    TBX3 is predominantly a transcriptional repressor.

    “Because TBX3 is predominantly a transcriptional repressor, they compared all genes bound by TBX3 to those upregulated in WD-fed Tbx3-knockout livers.”

  • The paper relies on this without support.

    TBX3 had not been previously linked to MASLD.

    “In this extended work, MOSAICS identified the transcription factor T-box 3 (TBX3) as a regulator of hepatic steatosis, which was noteworthy as TBX3 had not been previously linked to MASLD.”
2 of 2

Cites

Flagged first, then by citations

Cited by

Still being checked.

Authors
Maher, J. J.
Affiliations
University of California, San Francisco (US)
Corresponding author
Maher, Jacquelyn J.
ORCID
Maher, Jacquelyn J.
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2025-09-16
Volume
135
Issue
18
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
DOI
10.1172/jci197143
PMC
PMC12435830
OpenAlex
W4414195732
Semantic Scholar
291f43ef2bbfbbb1863e60be7025f96606f13c11
Cited by
0
References
18
FWCI
0.00
Type
journal article
Language
en
Open access
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)
Funders
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (RC2DK136052, P30DK026743)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
TBX3, non-alcoholic fatty liver disease, hepatic lipid accumulation, VLDL secretion, transcriptional repressor, loss-of-function mutations, hepatic lipid metabolism
MeSH terms
Loss of Function Mutation, Animals, Fatty Liver, Humans, Lipoproteins, VLDL, Liver, T-Box Domain Proteins, 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.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review