mTORC1-TFEB/TFE3 signaling is associated with bile acid diversification during hepatic metabolic adaptation

Zaufel A, Sun W, Pastore N, Taschler U, Wagner C, Hackl H, Sommer J, Silbert-Wagner D, Hengstler JG, Begher-Tibbe B, Stauber R, Kolb D · 2026 · Science Advances · Atlas ID ZAU2026

What this study shows

Establishes a new mTORC1-TFEB/TFE3 signaling axis controlling hepatic bile acid metabolism. Depending on mTORC1 signaling state, mice show coordinated shifts in bile-acid species (non-12-OH vs 12-OH) via altered enzyme expression and cholesterol trafficking; these shifts are reversed by mTORC1 pathway deletion or rapamycin treatment. Dietary protein restriction (which inhibits mTORC1) produces a similar bile-acid shift in mice and correlates with improved metabolic outcomes in human MASLD patients, linking mTORC1 nutrient sensing directly to bile-acid homeostasis and fatty liver disease.

Abstract

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The mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient and hormonal cues to regulate hepatic lipid metabolism with major implications for metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we show that altered hepatic mTORC1-TFEB/TFE3 signaling is associated with coordinated remodeling of bile acid (BA) metabolism during metabolic adaptation. Our data support a model in which cross-talk between mTORC1 and TFEB/TFE3 is associated with divergent regulation of bile acid synthesis and transformation.

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At a glance

Evidence type	A Animal model Marked A because it is an animal intervention or observation study measuring an organismal outcome (model: Mouse (liver-specific genetic mTORC1/TFEB manipulation, rapamycin treatment, dietary protein restriction); correlative human MASLD patient cohort); the code names the system studied -- animal work can be rigorous and still not be human data.
Study type	4 - Animal Study
Model system	Mouse (liver-specific genetic mTORC1/TFEB manipulation, rapamycin treatment, dietary protein restriction); correlative human MASLD patient cohort
Journal	Science Advances
Year	2026
Peer reviewed	Yes
Record last updated	2026-09-23
Source	DOI 10.1126/sciadv.aee1905 · PMID 42789715

Cite this paper

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Zaufel, A., Sun, W., Pastore, N., Taschler, U., Wagner, C., Hackl, H., Sommer, J., Silbert-Wagner, D., Hengstler, J. G., Begher-Tibbe, B., Stauber, R., Kolb, D., Troetzmueller, M., Gottschalk, B., Thorsheim, C., Stange, E. L., Hornef, M. W., Pivovarova-Ramich, O., Pfeiffer, A. F. H., Matchett, K. P., Loft, A., Herzig, S., Henderson, N. C., Ballabio, A., Arany, Z., Wolfrum, C., Fickert, P., & Moustafa, T. (2026). mTORC1-TFEB/TFE3 signaling is associated with bile acid diversification during hepatic metabolic adaptation. Science Advances. https://doi.org/10.1126/sciadv.aee1905

@article{ZAU2026,
  author       = {Zaufel, A. and Sun, W. and Pastore, N. and Taschler, U. and Wagner, C. and Hackl, H. and Sommer, J. and Silbert-Wagner, D. and Hengstler, J. G. and Begher-Tibbe, B. and Stauber, R. and Kolb, D. and Troetzmueller, M. and Gottschalk, B. and Thorsheim, C. and Stange, E. L. and Hornef, M. W. and Pivovarova-Ramich, O. and Pfeiffer, A. F. H. and Matchett, K. P. and Loft, A. and Herzig, S. and Henderson, N. C. and Ballabio, A. and Arany, Z. and Wolfrum, C. and Fickert, P. and Moustafa, T.},
  title        = {{mTORC1-TFEB/TFE3 signaling is associated with bile acid diversification during hepatic metabolic adaptation}},
  journal      = {Science Advances},
  year         = {2026},
  doi          = {10.1126/sciadv.aee1905},
  note         = {PMID: 42789715},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record ZAU2026) [Data set]. https://mtor-atlas.org/study/ZAU2026/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_ZAU2026,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record ZAU2026},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/ZAU2026/},
  doi          = {10.5281/zenodo.22059963}
}