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Tao, R.* ; Stöhr, O.* ; Tok, O.* ; Andres-Hernando, A.* ; Qiu, W.* ; He, B.* ; Wang, C.* ; Grøntved, L.* ; Burant, C.F.* ; Hui, S.T.* ; Lanaspa, M.A.* ; Stefan, N. ; Copps, K.D.* ; White, M.F.*

Fructose and follistatin potentiate acute MASLD during complete hepatic insulin resistance.

Nat. Commun. 16, 16 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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 13C incorporation into the glycerol backbone-but not fatty acid chains-of hepatic triacylglyceride after gavage with [U13C]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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Fatty Liver-disease; De-novo Lipogenesis; Nonalcoholic Steatohepatitis; Circulating Follistatin; Triglyceride Synthesis; Dietary Fructose; Innate Immunity; Nafld; Consequences; Dysfunction
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 16 Issue: 1, Pages: 16 Article Number: , Supplement: ,
Publisher Springer
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes Research and Metabolic Diseases (IDM)
Grants U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)
U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)