Human ATP–Binding Cassette G1 Controls Macrophage Lipoprotein Lipase Bioavailability and Promotes Foam Cell Formation

Abstract

Objective— The physiological function of the ATP–binding cassette G1 (ABCG1) transporter in humans is not yet elucidated, as no genetic disease caused by ABCG1 mutations has been documented. The goal of our study was, therefore, to investigate the potential role(s) of ABCG1 in lipid metabolism in humans. Methods and Results— Here we report that among the 104 polymorphisms present in the ABCG1 gene, the analysis of the frequent functional rs1893590 and rs1378577 single nucleotide polymorphisms located in the regulatory region of ABCG1 in the Regression Growth Evaluation Statin Study population revealed that both ABCG1 single nucleotide polymorphisms were significantly associated with plasma lipoprotein lipase (LPL) activity. Moreover, we observed that plasma LPL activity was modestly reduced in Abcg1 −/− mice as compared with control mice. Adipose tissue and skeletal muscle are the major tissues accounting for levels and activity of plasma LPL in the body. However, beyond its lipolytic action in the plasma compartment, LPL was also described to act locally at the cellular level. Thus, macrophage LPL was reported to promote foam cell formation and atherosclerosis in vivo. Analysis of the relationship between ABCG1 and LPL in macrophages revealed that the knockdown of ABCG1 expression (ABCG1 knockdown) in primary cultures of human monocyte–derived macrophages using small interfering RNAs led to a marked reduction of both the secretion and activity of LPL. Indeed, LPL was trapped at the cell surface of ABCG1 knockdown human monocyte–derived macrophages, likely in cholesterol-rich domains, thereby reducing the bioavailability and activity of LPL. As a consequence, LPL–mediated lipid accumulation in human macrophage foam cells in the presence of triglyceride-rich lipoproteins was abolished when ABCG1 expression was repressed. Conclusion— We presently report that ABCG1 controls LPL activity and promotes lipid accumulation in human macrophages in the presence of triglyceride-rich lipoproteins, thereby suggesting a potential deleterious role of macrophage ABCG1 in metabolic situations associated with high levels of circulating triglyceride-rich lipoproteins together with the presence of macrophages in the arterial wall.

Adipocyte ATP-Binding Cassette G1 Promotes Triglyceride Storage, Fat Mass Growth, and Human Obesity

“…Mobilization of free cholesterol in lipid droplets therefore provides an alternative pathway for the protection of adipocytes from toxicity. This study supports the notion that although the role of Abcg1 in cellular free cholesterol efflux mechanisms is crucial in maintaining tissue lipid homeostasis in a cholesterol-rich environment (2), Abcg1 contributes to cellular lipid (mostly TGs) accumulation and storage in highfat metabolic states (4,5). Thus, Abcg1 deficiency (30)(31)(32) as well as expression of human ABCG1 in mice (2,33) fed an atherogenic diet enriched in cholesterol highlights the role of Abcg1 in protecting tissues, especially the lung, from lipid accumulation without any apparent changes in adipose tissue mass or adiposity.…”

“…Lipid rafts in differentiated adipocytes was detected following incubation with 1 mg/mL Alexa Fluor 594-conjugated cholera toxin subunit-b (Molecular Probes) for 15 min at 4°C, as previously described (4,6). Indeed, binding of cholera toxin subunit-b to the pentasaccharide chain of plasma membrane ganglioside G M1 , which selectively partitions into lipid rafts (18), allows the reliable detection of lipid rafts in live cells.…”

“…1B). We previously reported that macrophage ABCG1 promotes TG storage by modulating LPL activity (4). To test whether the same mechanism operates in adipocytes, Abcg1 expression was silenced in 3T3-L1 preadipocytes using specific siRNAs that did not alter adipocyte differentiation and viability.…”

“…We recently reported that two frequent ABCG1 single nucleotide polymorphisms (SNPs) (rs1893590 and rs1378577) were significantly associated with plasma lipoprotein lipase (LPL) activity in the Regression Growth Evaluation Statin Study (REGRESS) population (4). Analysis of the relationship between the ABCG1 genotype and LPL led us to propose a mechanism by which ABCG1 controls macrophage LPL activity through modulation of membrane lipid rafts to promote intracellular lipid accumulation and foam cell formation in a triglyceride (TG)-rich context (4).…”

“…Analysis of the relationship between the ABCG1 genotype and LPL led us to propose a mechanism by which ABCG1 controls macrophage LPL activity through modulation of membrane lipid rafts to promote intracellular lipid accumulation and foam cell formation in a triglyceride (TG)-rich context (4). Thus, beyond a role in sterol export to HDL, ABCG1 may equally contribute to intracellular fatty acid accumulation and lipid storage in metabolic situations associated with increased concentrations of circulating TG-rich lipoproteins.…”