Reduced Expression of ATP-Binding Cassette Transporter G1 Increases Cholesterol Accumulation in Macrophages of Patients With Type 2 Diabetes Mellitus

Abstract

Background-Patients with type 2 diabetes mellitus are at increased risk for the development of atherosclerosis. A pivotal event in the development of atherosclerosis is macrophage foam cell formation. The ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 regulate macrophage cholesterol efflux and hence play a vital role in macrophage foam cell formation. We have previously found that chronic elevated glucose reduces ABCG1 expression. In the present study, we examined whether patients with type 2 diabetes mellitus had decreased ABCG1 and/or ABCA1, impaired cholesterol efflux, and increased macrophage foam cell formation. Methods and Results-Blood was collected from patients with and without type 2 diabetes mellitus. Peripheral blood monocytes were differentiated into macrophages, and cholesterol efflux assays, immunoblots, histological analysis, and intracellular cholesteryl ester measurements were performed. Macrophages from patients with type 2 diabetes mellitus had a 30% reduction in cholesterol efflux with a corresponding 60% increase in cholesterol accumulation relative to control subjects. ABCG1 was present in macrophages from control subjects but was undetectable in macrophages from patients with type 2 diabetes mellitus. In contrast, ABCA1 expression in macrophages was similar in both control subjects and patients with type 2 diabetes mellitus. Macrophage expression of ABCG1 in both patients and control subjects was induced by treatment with the liver X receptor agonist TO-901317. Upregulation of liver X receptor dramatically reduced foam cell formation in macrophages from patients with type 2 diabetes mellitus. Conclusions-ABCG1

Annexin A6 is highly abundant in monocytes of obese and type 2 diabetic individuals and is downregulated by adiponectin in vitro

“…Overexpression of annexin A6 in CHO cells disturbs cholesterol efflux (Cubells et al, 2007) and elevated annexin A6 in monocytes may contribute to reduced cholesterol release that has been described in type 2 diabetic monocytes (Li et al, 2008;Mauldin et al, 2008). Adiponectin stimulates cholesterol release in monocytic cells and besides induction of ABC transporters (Tsubakio-Yamamoto et al, 2008;Tian et al, 2009) the suppression of annexin A6 may reduce foam cell formation.…”

“…(B) Annexin A6 (Anx A6) and GAPDH in monocytes of 3 blood donors cultivated with or without 10 μg/ml adiponectin (Apm) for 24 h. (C) Annexin A6 (Anx A6) and GAPDH in monocytes cultivated with 2.5, 5.0, 7.5 or 10.0 μg/ml adiponectin for 24 h. (D) Annexin A6 and GAPDH in monocytes cultivated with 10 μg/ml adiponectin or without adiponectin for 12 h, 18 h, 24 h or 30 h. (E) Annexin A6 in monocytes cultivated with adiponectin, the p38 MAPK inhibitor SB 203580 or both for 24 h. (F) Annexin A6 in monocytes incubated with lovastatin or β-cyclodextrin for 16 h. type 2 diabetes or the metabolic syndrome. Indeed, while ABCA1 expression in diabetic monocytes was similar to control cells, ABCG1 expression was significantly reduced (Zhou et al, 2008;Mauldin et al, 2008).…”

“…In patients with the metabolic syndrome or type 2 diabetes mellitus low systemic HDL levels contribute to the higher risk and incidence of atherosclerotic disease (Bonora, 2006;Feig et al, 2008). These findings correlate with a 30% reduction in cholesterol efflux of monocyte-derived macrophages from patients with type 2 diabetes, indicating that initial steps in cholesterol export in diabetic patients are impaired (Mauldin et al, 2008). The molecular events in lipid efflux from monocytes are not fully understood, but recent studies point at the ATP-binding cassette transporters ABCA1 and ABCG1 as the main surface proteins that mediate cholesterol efflux to apolipoprotein A-I or HDL, respectively (Bodzioch et al, 1999;Klucken et al, 2000;Cavelier et al, 2006).…”

Glucose and Lipid Transporters Roles in Type 2 Diabetes

“…Therefore, GLUT12, like GLUT4, could become potentially critical to T2DM treatment in order to increase glucose uptake into the cell and reduce hyperglycemia. GLUT12 transporter mechanisms of action still need further study, including the degree to which its pathway is related to that of GLUT4 [13,20]. Another study appears to contradict the insulin responsive properties of GLUT12, finding that it does not respond to insulin in cardiomyocytes, but may do so in other tissues [21].…”

Efeitos do controle glicêmico sobre os lípides séricos e na transferência lipídica para a HDL em pacientes com diabetes mellitus tipo 2: novos achados no status do colesterol não esterificado

“…Ainda, no DM2 há uma diminuição da expressão do ABCA1, que parece estar relacionada com o aumento dos AGEs e ácidos graxos, hiperinsulinemia e com a própria inflamação gerada pelo DM2 (Uehara et al, 2002;Mcgillicuddy et al, 2005;Passarelli et al, 2005;Iborra et al, 2011;Park et al, 2012). O excesso de AGEs também leva a diminuição da expressão e função do ABCG1 (Ohgami et al, 2003;Mauldin et al, 2006Mauldin et al, , 2008Gantman et al, 2010;Iborra et al, 2011).…”