Critical Role of the Human ATP-Binding Cassette G1 Transporter in Cardiometabolic Diseases

Abstract

ATP-binding cassette G1 (ABCG1) is a member of the large family of ABC transporters which are involved in the active transport of many amphiphilic and lipophilic molecules including lipids, drugs or endogenous metabolites. It is now well established that ABCG1 promotes the export of lipids, including cholesterol, phospholipids, sphingomyelin and oxysterols, and plays a key role in the maintenance of tissue lipid homeostasis. Although ABCG1 was initially proposed to mediate cholesterol efflux from macrophages and then to protect against atherosclerosis and cardiovascular diseases (CVD), it becomes now clear that ABCG1 exerts a larger spectrum of actions which are of major importance in cardiometabolic diseases (CMD). Beyond a role in cellular lipid homeostasis, ABCG1 equally participates to glucose and lipid metabolism by controlling the secretion and activity of insulin and lipoprotein lipase. Moreover, there is now a growing body of evidence suggesting that modulation of ABCG1 expression might contribute to the development of diabetes and obesity, which are major risk factors of CVD. In order to provide the current understanding of the action of ABCG1 in CMD, we here reviewed major findings obtained from studies in mice together with data from the genetic and epigenetic analysis of ABCG1 in the context of CMD.

DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures

“…CpG methylation has shown to be driven by TG levels and not vice versa [ 24 ]. Although ABCG1 promotes the net cholesterol efflux to larger HDLs in the direct RCT pathway [ 62 , 63 ], and associations with ABCG1 transcription were found, no associations of cg06500161 with the cholesterol concentration or composition in HDLs were observed. Therefore, methylation at cg06500161 might be linked to a lower activity of TG-hydrolysis enzymes (e.g., lipoprotein lipase), which in turn enhances the indirect RCT pathway, and impedes observation of associations with cholesterol features in HDLs [ 15 , 25 ].…”

Targeting Foam Cell Formation in Atherosclerosis: Therapeutic Potential of Natural Products

“…At the transcriptional level, ABCG1 shares the common regulatory pathways of gene expression with ABCA1. The ABCG1 expression is upregulated by the nuclear receptors LXR, RXR, and PPAR activated by their agonists (oxysterols, retinoids, fatty acids, or synthetic agonists) (Venkateswaran et al, 2000;Hardy et al, 2017). Upregulation of ABCG1 expression mediated by LXR agonists probably involves the presence of multiple LXR responsive elements by the ABCG1 gene promoter and likely only requires the isoform LXRa in human macrophages (Sabol et al, 2005;Ishibashi et al, 2013).…”

HDL Cholesterol as a Marker of Disease Severity and Prognosis in Patients with Pulmonary Arterial Hypertension

“…By controlling secretion and activity of lipoprotein lipase and insulin, ABCG1 can impact the risk of cardiovascular diseases, including pulmonary circulation. Worth mentioning is the fact that most of the data on vasodilatatory functions of HDL are derived from animal models of systemic circulation [45]. Previous studies on peripheral artery reactivity in subjects with intermediate and high cardiovascular risk confirmed a strong association between both HDL cholesterol and apo-AI concentrations, and vasoreactivity of small resistance arteries [46].…”