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.
Highlights
Dyslipidemia is a main driver of cardiovascular diseases
To investigate the direct effect of lipid ingestion on adipose tissue macrophages (ATMs), we performed unbiased scRNA-seq of ATMs harvested from the epididymal adipose tissue (AT) of mice fed overnight with a high-fat diet (HFD) and mice kept on control chow diet (CD)
Unsupervised clustering based on shared and unique patterns of gene expression of 4358 ATMs from 6 fat pads (n = 3 CD pooled into 1 sample and n = 3 HFD pooled into 1 sample) identified 8 distinct populations that we visualized using uniform manifold approximation and projection (UMAP), revealing high ATM heterogeneity in lean mice (Fig. 1b)
Summary
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. Blocking the phosphatidylserine receptor Tim[4] inhibited lysosomal activation and the release of post-prandial high density lipoprotein cholesterol following a high fat meal. Clodronate-mediated cell-depletion implicated Tim4+ resident adipose tissue macrophages in this process These data indicate that Tim[4] is a key regulator of post-prandial cholesterol transport and adipose tissue macrophage function and may represent a novel pathway to treat dyslipidemia. The lipoprotein lipase (LPL), which is expressed at high levels in AT, hydrolyzes chylomicrons into fatty acids (FAs), allowing their preferential uptake and storage as TG in AT This process generates chylomicron remnants, poor in TG and rich in cholesterol, which are highly atherogenic[5]. Tim[4], a phosphatidylserine receptor, is present on numerous tissue-resident macrophages including the AT, but the relationship between dyslipidemia and Tim[4] has not been elucidated[26,27,28,29,30,31]
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