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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.*

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

Sci. Adv. 12:eaee1905 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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 type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 2375-2548
e-ISSN 2375-2548
Journal Science Advances
Quellenangaben Volume: 12, Issue: 39, Pages: , Article Number: eaee1905 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Publishing Place Washington, DC [u.a.]
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Cancer (IDC)