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

Abstract

The role of the ATP-binding cassette G1 (ABCG1) transporter in human pathophysiology is still largely unknown. Indeed, beyond its role in mediating free cholesterol efflux to HDL, the ABCG1 transporter equally promotes lipid accumulation in a triglyceride (TG)-rich environment through regulation of the bioavailability of lipoprotein lipase (LPL). Because both ABCG1 and LPL are expressed in adipose tissue, we hypothesized that ABCG1 is implicated in adipocyte TG storage and therefore could be a major actor in adipose tissue fat accumulation. Silencing of Abcg1 expression by RNA interference in 3T3-L1 preadipocytes compromised LPL-dependent TG accumulation during the initial phase of differentiation. Generation of stable Abcg1 knockdown 3T3-L1 adipocytes revealed that Abcg1 deficiency reduces TG storage and diminishes lipid droplet size through inhibition of Pparγ expression. Strikingly, local inhibition of adipocyte Abcg1 in adipose tissue from mice fed a high-fat diet led to a rapid decrease of adiposity and weight gain. Analysis of two frequent ABCG1 single nucleotide polymorphisms (rs1893590 [A/C] and rs1378577 [T/G]) in morbidly obese individuals indicated that elevated ABCG1 expression in adipose tissue was associated with increased PPARγ expression and adiposity concomitant to increased fat mass and BMI (haplotype AT>GC). The critical role of ABCG1 in obesity was further confirmed in independent populations of severe obese and diabetic obese individuals. This study identifies for the first time a major role of adipocyte ABCG1 in adiposity and fat mass growth and suggests that adipose ABCG1 might represent a potential therapeutic target in obesity.

The E3 Ubiquitin Ligases, HUWE1 and NEDD4-1, Are Involved in the Post-translational Regulation of the ABCG1 and ABCG4 Lipid Transporters

“…Although its individual role in the development of atherosclerosis in mouse models has at times been confusing, its important role in conjunction with ABCA1 in maintaining macrophage cholesterol homeostasis has been more evident (7). In addition, ABCG1 (in conjunction with ABCA1) has been implicated in the regulation of ␤-cell function and insulin secretion (8), and more recently in the regulation of triglyceride storage in adipocytes (9).…”

Adipose ABCG1: A potential therapeutic target in obesity?

“…However, our analysis of ABCG1 SNPs in 1320 morbidly obese patients revealed that both rs1378577 and rs1893590 were not associated with HOMA index independently of BMI. 3 More importantly, the deleterious effect of ABCG1 SNPs on BMI was not accompanied by any effect on diabetes or HOMA index. 3 Moreover, it is to note that neither a loss-of-function mutation nor a common variant in the ABCG1 gene were associated with Type 2 diabetes in 40,600 individuals of the Copenhagen City Heart Study (CCCHS) and the Copenhagen General Population Study (CGPS).…”

“…3 More importantly, the deleterious effect of ABCG1 SNPs on BMI was not accompanied by any effect on diabetes or HOMA index. 3 Moreover, it is to note that neither a loss-of-function mutation nor a common variant in the ABCG1 gene were associated with Type 2 diabetes in 40,600 individuals of the Copenhagen City Heart Study (CCCHS) and the Copenhagen General Population Study (CGPS). 9 Numerous observations validated the positive association between Abcg1 expression and AT formation and growth.…”

“…Deciphering the underlying mechanism led us to conclude that ABCG1-mediated sphingomyelin (SM) efflux is required for optimal LPL activity and TG storage in adipocytes. 3 Moreover, our translational in vivo studies in mice and in obese patients uncovered the deleterious role of ABCG1 in AT formation and obesity, allowing us to suggest that ABCG1 can represent a novel therapeutic target in obesity. 6 This hypothesis is reinforced by the previously unexpected observation that total ablation of Abcg1 in mice protects from diet-induced obesity as illustrated by reduced fat mass and body weight gain in Abcg1 -/-animals as compared to control Abcg1 C/C littermates.…”

“…Very recently, we identified a new actor in TG storage in adipocyte which contributes to fat mass formation and development of obesity in humans. 3 Specifically, we reported that the membrane ATPBinding Cassette G1 transporter (ABCG1) promotes LPL-dependent TG storage in adipocyte and activates adipogenic transcriptional program controlled by PPAR (peroxisome proliferator-activated receptor)g (Fig. 1).…”