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<p>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 <i>NRAC</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月1日

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  • Inderjeet Singh,
  • Yasuhiro Onogi,
  • Filipe Menezes,
  • Dina Khasanova,
  • Lingru Kang,
  • Chenxi Wang,
  • Julio Ruiz-Trave,
  • Sapna Sharma,
  • Ahmed Khalil,
  • Valentin K Reichenbach,
  • Yingzi Shi,
  • Andrew Flatley,
  • Xiaocheng Yan,
  • Andreas Israel,
  • Nathalia R V Dragano,
  • Juan Antonio Aguilar-Pimentel,
  • Anne Hoffmann,
  • Adhideb Ghosh,
  • Falko Noé,
  • Christian Wolfrum,
  • Sebastian Cucuruz,
  • Ann-Christine König,
  • Ingo Burtscher,
  • Stefanie M Hauck,
  • Heiko Lickert,
  • Susanna M Hofmann,
  • Regina Feederle,
  • Sonja C Schriever,
  • Rene Hernandez-Bautista,
  • Gencer Sancar,
  • Alberto Cebrian-Serrano,
  • Igor Tetko,
  • Helmut Fuchs,
  • Valérie Gailus-Durner,
  • Matthias Blüher,
  • Martin Hrabě de Angelis,
  • Siegfried Ussar

摘要

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.