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Singh, I. ; Onogi, Y. ; Cardoso Micu Menezes, F.M. ; Khasanova, D. ; Kang, L. ; Wang, C. ; Ruiz-Trave, J. ; Sharma, S. ; Khalil, A. ; Reichenbach, V.K. ; Shi, Y. ; Flatley, A. ; Yan, X. ; Israel, A. ; Dragano, N.R.V. ; Aguilar-Pimentel, J.A. ; Hoffmann, A. ; Ghosh, A.* ; Noé, F.* ; Wolfrum, C.* ; Cucuruz, S. ; König, A.-C. ; Burtscher, I. ; Hauck, S.M. ; Lickert, H. ; Hofmann, S.M. ; Feederle, R. ; Schriever, S.C. ; Hernandez-Bautista, R. ; Sancar, G.* ; Cebrian Serrano, A. ; Tetko, I.V. ; Fuchs, H. ; Gailus-Durner, V. ; Blüher, M. ; Hrabě de Angelis, M. ; Ussar, S.

NRAC controls CD36-mediated fatty acid uptake in adipocytes and lipid clearance in vivo.

EMBO J. 44, 5037-5065 (2025)
Publ. Version/Full Text Research data DOI PMC
Creative Commons Lizenzvertrag
Open Access Green as soon as Postprint is submitted to ZB.
Adipose tissue is a central organiser of systemic lipid homeostasis and a pharmacological target in obesity, orchestrating cellular responses to environmental cues. Nutritionally regulated adipose and cardiac enriched protein (NRAC) is a small adipocyte-specific transmembrane protein with unknown function. Here, we show that Nrac directly interacts with scavenger receptor CD36 via its first transmembrane domain. Forming a complex with CD36 and caveolin-1 under low extracellular fatty acid (FA) concentrations, NRAC modulates CD36-dependent fatty acid uptake in adipocytes. Upon increase in extracellular FA levels, NRAC is ubiquitinated and internalised, leading to CD36's dissociation from caveolin-1 and clathrin-mediated endocytosis. This results in increased fatty acid uptake into fat cells, adipocyte hypertrophy, increased fat mass and elevated lipid clearance from the blood in chow-diet-fed mice. Finally, human NRAC expression and the intronic SNP rs12878589 are associated with body fat distribution and obesity. Together, these findings reveal a novel regulatory mechanism by which adipocytes sense and respond to extracellular fatty acid availability to fine-tune lipid uptake and storage at cellular and organismal level.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Adipose Tissue ; Cd36 ; Clathrin-mediated Endocytosis ; Fatty Acid Uptake ; Hypertrophy; Adipose; Insulin; Obesity; Brown
ISSN (print) / ISBN 0261-4189
e-ISSN 1460-2075
Journal EMBO Journal, The
Quellenangaben Volume: 44, Issue: 18, Pages: 5037-5065 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Heidelberg, Germany
Reviewing status Peer reviewed
Institute(s) Adipocytes & Metabolism (ADM)
Institute of Diabetes and Obesity (IDO)
Institute of Structural Biology (STB)
Institute of Epidemiology (EPI)
CF Monoclonal Antibodies (CF-MAB)
Institute of Experimental Genetics (IEG)
Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Institute of Diabetes and Regeneration Research (IDR)
CF Metabolomics & Proteomics (CF-MPC)
Grants Projekt DEAL
Uehara Memorial Foundation, Japan
Alexander von Humboldt-Stiftung, Germany
China Scholarship Council
Horizon Europe funding programme under the Marie Sklodowska-Curie Actions Doctoral Networks
German Federal Ministry of Education and Research
German Center for Diabetes Research (DZD) (MHdA)
DFG
Deutsches Zentrum fur Diabetesforschung (DZD)
National Overseas Scholarship from the Government of India