Fructose and follistatin potentiate acute MASLD during complete hepatic insulin resistance
MASLD (metabolic-associated steatotic liver disease) and MASH (steatohepatitis) are closely associated with hepatic IR (insulin resistance) and T2D. Regardless, insulin-stimulated hepatic lipogenesis is considered essential for MASLD development, as mouse models of complete hepatic IR become diabetic without MASLD when fed high-fat diets. Challenging this notion, we found that male LDKO mice lacking hepatic insulin receptor substrates acutely developed MASLD if fed a fructose-enriched "MASH diet" (GAN) or high-fructose diet. Fructose potentiated hepatic re-esterification of abundant circulating fatty acids in LDKO mice, evidenced by excess <sup>13</sup>C incorporation into the glycerol backbone-but not fatty acid chains-of hepatic triacylglyceride after gavage with [U<sup>13</sup>C]fructose. Suppressing adipose lipolysis in LDKO mice by inactivating hepatic Fst (Follistatin) prevented acute MASLD, whereas over-expressing Fst in wild-type mouse liver accelerated GAN-promoted MASLD/MASH. Compatibly, higher serum FST levels among Tübingen Diabetes Family Study participants clustered with increased adipose IR and greater hepatic triacylglyceride accumulation.
Authors
- Norbert Stefan (ORCID: https://orcid.org/0000-0002-2186-9595)
- Lars Grøntved (ORCID: https://orcid.org/0000-0002-6735-8483)
- Rongya Tao (ORCID: https://orcid.org/0000-0002-6797-7006)
- Kyle D. Copps
- Miguel A. Lanaspa (ORCID: https://orcid.org/0000-0002-1163-1831)
- Ana Andrés-Hernando (ORCID: https://orcid.org/0000-0002-0676-0188)
- Ben He (ORCID: https://orcid.org/0000-0002-6717-9039)
- Oliver Stöhr
- Wei Qiao Qiu (ORCID: https://orcid.org/0000-0002-2082-2410)
- Morris F. White (ORCID: https://orcid.org/0000-0003-2166-508X)
- Charles Burant (ORCID: https://orcid.org/0000-0001-9189-5003)
- Sheng Hui (ORCID: https://orcid.org/0000-0002-4226-6806)
- Özlem Tök (ORCID: https://orcid.org/0000-0002-1778-5233)
- Caixia Wang (ORCID: https://orcid.org/0000-0001-6314-7286)
Institutions
- Boston Children's Hospital (US)
- Harvard University (US)
- University of Southern Denmark (DK)
- University of Michigan (US)
- Universitätsklinikum Tübingen (DE)
- Michigan Medicine (US)
- University Children's Hospital Tübingen (DE)
- Deutsches Diabetes-Zentrum e.V. (DE)
- German Center for Diabetes Research (DE)
- Institute of Diabetes Research
- Heinrich Heine University Düsseldorf (DE)
- University of Colorado Anschutz Medical Campus (US)
- University of Tübingen (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-24
- DOI
- https://doi.org/10.1038/s41467-025-66296-5
- Citations
- 1
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 1.35
Funders
- National Institutes of Health