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Role of Tim4 in the regulation of ABCA1+ adipose tissue macrophages and post-prandial cholesterol levels

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  • Marlene Magalhaes
  • Peter Smith
  • Jordan Portman
  • Lucy Jackson-Jones
  • Calum Bain
  • Prakash Ramachandran
  • Zoi Michalidou
  • Roland Stimson
  • Marc Dweck
  • Laura Denby
  • Neil Henderson
  • Stephen Jenkins
  • Cecile Benezech
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Article number4434
<mark>Journal publication date</mark>21/07/2021
<mark>Journal</mark>Nature Communications
Volume12
Number of pages15
Publication StatusPublished
<mark>Original language</mark>English

Abstract

Dyslipidemia is a main driver of cardiovascular diseases. The ability of macrophages to scavenge excess lipids implicate them as mediators in this process and understanding the mechanisms underlying macrophage lipid metabolism is key to the development of new treatments. Here, we investigated how adipose tissue macrophages regulate post-prandial cholesterol transport. Single-cell RNA sequencing and protected bone marrow chimeras demonstrated that ingestion of lipids led to specific transcriptional activation of a population of resident macrophages expressing Lyve1, Tim4, and ABCA1. Blocking the phosphatidylserine receptor Tim4 inhibited lysosomal activation and the release of post-prandial high density lipoprotein cholesterol following a high fat meal. Both effects were recapitulated by chloroquine, an inhibitor of lysosomal function. Moreover, clodronate-mediated cell-depletion implicated Tim4+ resident adipose tissue macrophages in this process. Thus, these data indicate that Tim4 is a key regulator of post-prandial cholesterol transport and adipose tissue macrophage function and may represent a novel pathway to treat dyslipidemia.