PuSH - Publication Server of Helmholtz Zentrum München: NRAC controls CD36-mediated fatty acid uptake in adipocytes and lipid clearance in vivo.

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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)

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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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