3B) did display significantly greater swelling for CR over AL cells (p<0.004, n=3). ABCG1 is likely produced by cholesterol loaded ATMs since this gene is not CHIR-124 highly indicated in adipocytes and ABCG1 manifestation is definitely sterol mediated. Our data supports the concept that metabolic changes in adipocytes due to demand lipolysis and cell death lead to cholesterol loading of ATMs. Based on getting cholesterol-loaded peritoneal leukocytes with elevated levels of ABCG1 in CR as compared to AL mice, we suggest that pathways for cholesterol trafficking out of adipose cells involve ATM egress as well as ABCG1 mediated cholesterol efflux. Keywords:ABCG1, ABCA1, cholesterol efflux, obesity, caloric restriction, mice == 1. Introduction == The prevalence of obesity has reached epidemic proportions and is associated with several co-morbid conditions including diabetes, dyslipidemia, malignancy, atherosclerosis and gallstones [1-3]. The dyslipidemia is usually characterized by high levels of circulating triglyceride-rich lipoproteins and low density lipoproteins (LDL), and reduced levels of high density lipoproteins (HDL). The reduced levels of HDL are troubling because HDL and its major apolipoprotein (apo), apoA1, participate in removing excessive free cholesterol from peripheral tissues to the liver for subsequent catabolism and excretion through processes involved in reverse cholesterol transport [4,5]. In addition, HDL have been show to have anti-inflammatory properties [6-9]. These HDL activities have been shown to provide crucial pathways of protection from atherosclerosis (examined by [10]), a vascular disease characterized by inflammation and cholesterol accumulation. Obesity is also characterized by inflammation as evidenced by elevations in circulating inflammatory cytokines and the accumulation of adipose tissue macrophages (ATMs) [11] and as examined [12]. Further, adipocytes contain large amounts of free cholesterol that must be mobilized during lipolysis. Since lipolysis occurs at CHIR-124 a high rate in obesity [13] especially during demand lipolysis driven by weight loss regimes [14], efficient cholesterol efflux mechanisms are needed. Thus, it is possible that reduced HDL levels may also be deleterious for obesity. Adipocytes contain large amounts of free cholesterol that serve to maintain the monolayer surrounding the triacylglycerol lipid droplet and support the structure and function of the plasma membrane [15,16]. In humans, adipose tissue contains the largest pool of free cholesterol in the body, which is usually estimated at 25% of total body cholesterol [17-19] (1.6 mg/g adipose lipid). The amount of free cholesterol can double in obese individuals [20], approaching 50 g of total adipose cholesterol [18,19]. In fact, adipose tissue is usually thought to provide a buffer for cholesterol storage because free cholesterol levels in adipose tissue increase in hypercholesterolemic animals [21] and humans [22]. In mature rats, adipose tissue constitutes nearly 3% of total carcass cholesterol (~1 mg/g lipid in epididymal excess fat). Cholesterol levels increase to nearly 13% in genetically obese littermates [23]. Since adipocytes are unable to catabolize cholesterol, the efflux of extra free cholesterol is crucial for preserving cholesterol homeostasis. CHIR-124 However, mechanisms by which cholesterol is usually mobilized in and removed from adipose tissue during obesity and weight loss are not known. Several receptors facilitate cholesterol efflux in most cell types including ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1) and scavenger receptor class B type I (SR-BI). Their relative contributions to efflux in adipocytes are unclear especially during SOS2 stimulated lipolysis occurring with caloric restriction. ABCA1 and ABCG1 are sterol-inducible transmembrane proteins [24]. ABCA1 is usually important for the cellular efflux of free cholesterol and phospholipid to lipid-poor apolipoproteins (apos) such as apoA-I [25-27]. ABCG1 is usually associated with cholesterol efflux to HDL [28]. ABCA1 is required to maintain plasma HDL cholesterol levels [26]. In contrast, ABCG1 is not as mice deficient [29] or overexpressing this transporter [30] show no changes in plasma total or HDL cholesterol levels. SR-BI is usually a multi-ligand receptor that mediates the binding and bi-directional flux of cholesterol. The net movement of free cholesterol depends on the direction of CHIR-124 the cholesterol gradient CHIR-124 [31]. Like ABCA1, SR-BI is usually expressed in differentiated 3T3-L1 adipocytes [32]. However, little is known about the function of SR-BI in adipose tissuein vivo, particularly the extent to which it contributes to cholesterol efflux. Recently, an elegantin vivostudy exhibited that cholesterol efflux from adipocytes is usually mediated by ABCA1 and SR-B1 but not ABCG1 [33]. Further, 3T3-L1 cell culture studies show that apoA-I increases cholesterol efflux from lipid loaded adipocytes in a time-dependent manner [34,35]. But ABCG1 may.
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