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Title: Regulation of ATP-binding cassette transporters and cholesterol efflux by glucose in primary human monocytes and murine bone marrow-derived macrophages

Author
item SPARTANO, NICOLE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item LAMON-FAVA, STEFANI - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item MATTHAN, NIRUPA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item RONXHI, JANEY - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item GREENBERG, ANDREW - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item OBIN, MARTIN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item LICHTENSTEIN, ALICE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Experimental and Clinical Endocrinology & Diabetes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/2/2014
Publication Date: N/A
Citation: N/A

Interpretive Summary: Individuals with type 2 diabetes mellitus are at increased risk of developing heart disease. This may be partially attributable to a disruption in the mechanisms by which cholesterol is transported out of cells, which would favor accumulation. Accumulation of cholesterol in cells results in the development of fatty plaque in blood vessels that fed the heart, causing narrowing, leading to the development of heart disease. Sustained elevation of blood glucose (sugar) concentrations is thought to impede cholesterol transport out of cells. Two models were used to test this hypothesis; white blood cells isolated from individuals after they were given a large dose of glucose and mouse bone marrow-derived macrophages (BMDM) = cultured in media with different concentrations of glucose. The expression of a cholesterol transporter, ABC-transporter mRNA, was monitored. In a separate study, mouse-BMDM were maintained in culture and exposed to glucose with and without oxidized low density lipoprotein (as a source of cholesterol). An acceptor of cholesterol transported out of the cell, high density lipoprotein (HDL), was added and cholesterol efflux and cholesterol transporter expression were determined. In humans, one hour post-glucose challenge there was no significant change in white blood cell cholesterol transporter expression. In mice BMDM, higher glucose concentrations suppressed HDL-mediated cholesterol efflux without significantly altering cholesterol transporter gene expression. Human white blood cell cholesterol transporter gene expression was unresponsive to a glucose challenge. Correspondingly, in BMDM, high glucose concentrations attenuated cholesterol efflux in the absence of altered cholesterol transporter expression, suggesting that high glucose concentrations, per se, suppress cholesterol transporter activity. This glucose-related impairment in cholesterol efflux may potentially contribute to diabetes-associated atherosclerosis.

Technical Abstract: 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. Two models were used to assess this potential relationship: human monocytes/leukocytes and murine bone marrow-derived macrophages (BMDM). Ten subjects (4F/6M, 50-85yrs, BMI 25-35kg/m**(2)) underwent an oral glucose challenge. Baseline and 1- and 2-hour 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 5mmol/L D-glucose (control) or additional 20mmol/L D- or L-glucose and 25ug/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). One hour 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.