Regulation of ATP-binding cassette transporters and cholesterol efflux by glucose in primary human monocytes and murine bone marrow-derived macrophages.
Individuals with type 2 diabetes mellitus are at increased risk of developing atherosclerosis. This may be partially attributable to suppression of macrophage ATP-binding cassette (ABC) transporter mediated cholesterol efflux by sustained elevated blood glucose concentrations. 2 models were used to assess this potential relationship: human monocytes/leukocytes and murine bone marrow-derived macrophages (BMDM).10 subjects (4 F/6 M, 50-85 years, BMI 25-35 kg/m²) underwent an oral glucose challenge. Baseline and 1- and 2-h post-challenge ABC-transporter mRNA expression was determined in monocytes, leukocytes and peripheral blood mononuclear cells (PBMC). In a separate study, murine-BMDM were exposed to 5 mmol/L D-glucose (control) or additional 20 mmol/L D- or L-glucose and 25 ug/mL oxidized low density lipoprotein (oxLDL). High density lipoprotein (HDL)-mediated cholesterol efflux and ABC-transporter (ABCA1 and ABCG1) expression were determined.Baseline ABCA1and ABCG1 expression was lower (>50%) in human monocytes and PBMC than leukocytes (p<0.05). 1 h post-challenge leukocyte ABCA1 and ABCG1 expression increased by 37% and 30%, respectively (p<0.05), and began to return to baseline thereafter. There was no significant change in monocyte ABC-transporter expression. In murine BMDM, higher glucose concentrations suppressed HDL-mediated cholesterol efflux (10%; p<0.01) without significantly affecting ABCA1 and ABCG1 expression. Data demonstrate that leukocytes are not a reliable indicator of monocyte ABC-transporter expression.Human monocyte ABC-transporter gene expression was unresponsive to a glucose challenge. Correspondingly, in BMDM, hyperglycemia attenuated macrophage cholesterol efflux in the absence of altered ABC-transporter expression, suggesting that hyperglycemia, per se, suppresses cholesterol transporter activity. This glucose-related impairment in cholesterol efflux may potentially contribute to diabetes-associated atherosclerosis.
Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, United States.
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Spartano
Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, United States.
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Lamon-Fava
Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, United States.
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Matthan
Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, United States.
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Ronxhi
Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, United States.
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Greenberg
Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, United States.
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Obin
Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, United States.
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Lichtenstein
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D002784:Cholesterol; D005947:Glucose