Year: 2025
Type: article
Abstract: 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. The authors report that, in mice without hepatic insulin signaling, diets high in fructose cause acute hepatic steatosis without increasing hepatic de novo lipogenesis, dependent upon hepatic follistatin secretion and associated adipose insulin resistance.
Source: Nature Communications
Authors: Rongya Tao, Oliver Stöhr, Ozlem Tok, Ana Andres-Hernando, Wei Qiu, Baiyu He, Caixia Wang, Lars Grøntved, Charles Burant, Sheng Hui, Miguel A. Lanaspa, Norbert Stefan, Kyle D. Copps, Morris F. White
Institutions: Boston Children's Hospital, Harvard University, University of Colorado Anschutz, University of Colorado Denver, University of Southern Denmark, University of Michigan, Michigan Medicine, Universitätsklinikum Tübingen, German Center for Diabetes Research, Institute of Diabetes Research, University of Tübingen
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G1298852148, Hepatic insulin resistance integrates T2D and NAFLD, G209660933, G2677166738, G270618122, G321008341, G3278896972, G383794702, Targeting fructokinase, endogenous fructose production and purine degradation for the prevention and treatment of hereditary fructose intolerance, G3956656220, G3987543772, G4196591811, G4541629867, G4715718774, G4806582355, G6090905776, G6397133344, G6652606157, G6681835452, G6798762231, Regulation of hippocampal function by central and peripheral IRS signaling, G7307262795, Anatomical Regulation of Glucose and Lipid Metabolism by Insulin Signaling in Hepatocytes, Metabolic Crosstalk During Hepatic Insulin Resistance, G8460726001, G9000232081, G9000242881, G9000309072, Role of TAZ in metabolic regulation in both normal and insulin resistant states
OpenAlex ID: W4416624578