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

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. Depending on the mTORC1 signaling state, changes in hepatic Cyp2c70 and Cyp8b1 expression, together with altered cholesterol trafficking, were associated with shifts toward non–12-OH or 12-OH bile acid species. These effects were attenuated or reversed by Tfe3 deletion or rapamycin treatment. Furthermore, protein restriction (which inhibits mTORC1) similarly reshaped the BA profile in mice and correlated with improved metabolic outcomes in MASLD patients. Together, these findings uncover BA homeostasis as an integral component of the metabolic adaptations orchestrated by mTORC1, underscoring a link between nutrient signaling and metabolic liver disease.

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Publication Details

Journal
Science Advances
Published
2026-09-25
DOI
https://doi.org/10.1126/sciadv.aee1905
Primary Topic
Liver Disease Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
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article

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

Nunzia Pastore, Carina Wagner, Zoltan Pierre Arany, Kolb Dagmar et al.
Science Advances
Liver Disease Diagnosis and Treatment
article

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

Nunzia Pastore, Carina Wagner, Zoltan Pierre Arany, Kolb Dagmar, Wenfei Sun, Alex Zaufel, Olga Pivovarova‐Ramich, Christian Wolfrum, Ulrike Taschler, Tarek M. Moustafa, Brigitte Begher‐Tibbe, Rudolf E Stauber, Mathias Walter Hornef, Chelsea L. Thorsheim, Hubert Hackl, Dagmar Silbert-Wagner, Benjamin Gottschalk, Martin Trötzmüller, Peter Fickert, Kylie P. Matchett, Eva-Lena Stange, Stephan Herzig, Andreas F. H. Pfeiffer, Judith Sommer, Andrea Ballabio, Neil Cowan Henderson, Anne Loft, Jan G. Hengsler
article en

Abstract

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. Depending on the mTORC1 signaling state, changes in hepatic Cyp2c70 and Cyp8b1 expression, together with altered cholesterol trafficking, were associated with shifts toward non–12-OH or 12-OH bile acid species. These effects were attenuated or reversed by Tfe3 deletion or rapamycin treatment. Furthermore, protein restriction (which inhibits mTORC1) similarly reshaped the BA profile in mice and correlated with improved metabolic outcomes in MASLD patients. Together, these findings uncover BA homeostasis as an integral component of the metabolic adaptations orchestrated by mTORC1, underscoring a link between nutrient signaling and metabolic liver disease.

Science AdvancesVol. 12(39)
Innsbruck Medical University (AT), University of Graz (AT), Palo Alto University (US), University of Southern Denmark (DK), Baylor College of Medicine (US), Universität Innsbruck (AT), TU Dortmund University (DE), Medical University of Graz (AT), ETH Zurich (CH), Humboldt-Universität zu Berlin (DE), Neurological Research Institute (US), Federico II University Hospital (IT), Westfälische Hochschule (DE), Texas Children's Hospital (US), Centre for Inflammation Research (GB), Telethon Institute Of Genetics And Medicine (IT), Deutsches Diabetes-Zentrum e.V. (DE), Institute of Genetics and Cancer (GB), German Center for Diabetes Research (DE), German Institute of Human Nutrition (DE), Leibniz Research Centre for Working Environment and Human Factors (DE), Institute of Food, Nutrition, and Health (CH), Heinrich Heine University Düsseldorf (DE), University of Pennsylvania (US), Stanford University (US), University of Edinburgh (GB)
Openalex Percentile: Top 11%
Liver Disease Diagnosis and Treatment
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