Hematopoietic ABCA1 deletion promotes monocytosis and worsens diet-induced insulin resistance in mice

Tang, Chongren; Liu, Yuhua; Yang, Wenbo; Storey, Carl; McMillen, Timothy S.; Houston, Barbara; Heinecke, Jay W.; LeBoeuf, Renée C.

doi:10.1194/jlr.m064303

Cited by 12 publications

(7 citation statements)

References 35 publications

(31 reference statements)

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“…Even though there are studies in mouse models and isolated adipocytes suggesting the possible role of ABCA1 in adipocytes in modulating insulin sensitivity,11,12 we could not find any study suggesting a similar role in humans. Similar studies by Key et al and Tang et al in mouse models with cell-specific ABCA1 knockout in hepatocytes19 and hematopoietic cells,20 respectively, suggest that ABCA1 modulates insulin sensitivity. The present study suggests a possible role of adipose tissue ABCA1 in modulating the insulin resistance associated with obesity in humans.…”

Section: Discussionsupporting

confidence: 70%

<p>ATP-binding cassette transporter A1 (ABCA1) expression in adipose tissue and its modulation with insulin resistance in obesity</p>

Vincent¹,

Thakkar²,

Aggarwal³

et al. 2019

DMSO

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Purpose Adipose tissue dysfunction is at the center of metabolic dysfunctions associated with obesity. Through studies in isolated adipocytes and mouse models, ATP-binding cassette transporter A1 (ABCA1) expression in the adipose tissue has been shown to regulate high-density lipoprotein (HDL) cholesterol levels in the circulation and insulin sensitivity at both adipose tissue and whole-body levels. We aimed to explore the possible link between ABCA1 expression in the adipose tissue and metabolic derangements associated with obesity in humans. Patients and methods This exploratory study among individuals who were lean (body mass index [BMI]: 22.3±0.34 kg/m 2 , n=28) and obese (BMI: 44.48±5.3 kg/m 2 , n=34) compared the expression of ABCA1, adiponectin and GLUT4 (SLC2A4) in visceral and subcutaneous adipose tissue using quantitative real-time PCR and immunohistochemistry. Homeostatic model assessment for insulin resistance (HOMA-IR) and adipose tissue insulin resistance (adipo-IR) were used as insulin resistance markers. Results Visceral adipose tissue from individuals who were obese had significantly lower ABCA1 ( P =0.04 for mRNA and protein) and adiponectin ( P =0.001 for mRNA) expression compared to that from lean individuals. Subcutaneous adipose tissue did not show any significant difference in the expression. When individuals were divided into insulin-sensitive (IS) and insulin-resistant (IR) groups based on HOMA-IR, IR individuals had lower ABCA1 ( P =0.0001 for mRNA and P =0.009 for protein) expression compared to IS individuals in visceral adipose tissue, but not in subcutaneous adipose tissue. The difference was significant after adjusting for age, gender and BMI. ABCA1 mRNA expression in visceral adipose tissue correlated negatively with both HOMA-IR ( r =−0.44, P =0.0003) and adipo-IR ( r =−0.35, P =0.005) after adjusting for age, gender and BMI. ABCA1 expression in either visceral or subcutaneous adipose tissue did not have any significant correlation with HDL cholesterol levels or mean adipocyte area. Conclusion Obesity and insulin resistance are associated with lower expression of ABCA1 in visceral adipose tissue in humans.

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Section: Discussionsupporting

confidence: 70%

<p>ATP-binding cassette transporter A1 (ABCA1) expression in adipose tissue and its modulation with insulin resistance in obesity</p>

Vincent¹,

Thakkar²,

Aggarwal³

et al. 2019

DMSO

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show abstract

“…ABCA1 is required for lipogenesis and lipid accretion in adipocytes during diet-induced obesity 10 . In hematopoietic cells, ABCA1 limits inflammation, the recruitment of monocytes and macrophages to AT, and protects against diet-induced insulin resistance 11 . In humans, obesity and insulin resistance have been associated with lower ABCA1 expression in AT 12 .…”

mentioning

confidence: 99%

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

et al. 2021

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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.

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“…Intracellular Chol levels are linked to impaired glucose tolerance and IR and as such, Abca1 hematopoietic deletion not only induced monocytosis and increased inflammatory cytokine and macrophage content in both AT and liver, but also enhanced ATM response to saturated FA (SFA). Hematopoietic Abca1 -/mice fed a diabetogenic diet supplemented with Chol were thus more insulin resistant [63]. While seemingly logic, these results have been contested by experiments conducted in myeloid Abca1 KO and Wt mice who developed similar IR, hypercholesterolemia and hepatic steatosis.…”

Section: Lipid Efflux/exportmentioning

confidence: 99%

Rewiring of Lipid Metabolism in Adipose Tissue Macrophages in Obesity: Impact on Insulin Resistance and Type 2 Diabetes

Dahik

Frisdal

Goff

2020

IJMS

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Obesity and its two major comorbidities, insulin resistance and type 2 diabetes, represent worldwide health issues whose incidence is predicted to steadily rise in the coming years. Obesity is characterized by an accumulation of fat in metabolic tissues resulting in chronic inflammation. It is now largely accepted that adipose tissue inflammation underlies the etiology of these disorders. Adipose tissue macrophages (ATMs) represent the most enriched immune fraction in hypertrophic, chronically inflamed adipose tissue, and these cells play a key role in diet-induced type 2 diabetes and insulin resistance. ATMs are triggered by the continuous influx of dietary lipids, among other stimuli; however, how these lipids metabolically activate ATM depends on their nature, composition and localization. This review will discuss the fate and molecular programs elicited within obese ATMs by both exogenous and endogenous lipids, as they mediate the inflammatory response and promote or hamper the development of obesity-associated insulin resistance and type 2 diabetes.

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Hematopoietic ABCA1 deletion promotes monocytosis and worsens diet-induced insulin resistance in mice

Cited by 12 publications

References 35 publications

<p>ATP-binding cassette transporter A1 (ABCA1) expression in adipose tissue and its modulation with insulin resistance in obesity</p>

<p>ATP-binding cassette transporter A1 (ABCA1) expression in adipose tissue and its modulation with insulin resistance in obesity</p>

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

Rewiring of Lipid Metabolism in Adipose Tissue Macrophages in Obesity: Impact on Insulin Resistance and Type 2 Diabetes

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