Journal Article

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

Dweck, M. R., Michailidou, Z., Jenkins, S. J., Bain, C. C., Smith, P., Portman, J. R., Ramachandran, P., Denby, L., Magalhaes, M. S., Jackson-Jones, L. H., Stimson, R. H., Henderson, N. C., Bénézech, C.

2021

Overview

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. Diverse macrophage subsets are found in adipose tissue where they regulate its physiology. Here, the authors used single-cell RNA sequencing to analyse the effect of post-prandial lipids on adipose tissue macrophages and identify Tim4 as a regulator of ABCA1 + macrophage function and post-prandial cholesterol transport.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/31 / 13/51 / 38/39 / 49/91 / 631/250/2504/342 / 631/443/319/2723 / 64/60 / 692/4019/592/75/2099 / ABCA1 protein / Adipose tissue / Adipose Tissue - cytology / Adipose Tissue - metabolism / Animals / ATP Binding Cassette Transporter 1 - metabolism / ATP-binding protein / Bisphosphonates / Bone marrow / Cardiovascular diseases / Chimeras / Chloroquine / Cholesterol / Cholesterol - metabolism / Cholesterol, HDL - metabolism / Clodronic acid / Depletion / Diet, High-Fat / Dyslipidemia / Gene sequencing / Humanities and Social Sciences / Ingestion / Lipid Metabolism / Lipids / Lysosomes - metabolism / Macrophages / Macrophages - cytology / Macrophages - metabolism / Membrane Proteins - metabolism / Metabolic disorders / Mice / multidisciplinary / Obesity - metabolism / Obesity - pathology / Phosphatidylserine / Postprandial Period - physiology / RNA transport / Science / Science (multidisciplinary) / Transcription activation / Transcriptional Activation / Vesicular Transport Proteins - metabolism