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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #307545
Title: Linoleic acid suppresses cholesterol efflux and ATP-binding cassette transporters in murine bone marrow-derived macrophages

Author
item SPARTANO, NICOLE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item LAMON-FAVA, STEFANIA - 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 OBIN, MARTIN - 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 LICHTENSTEIN, ALICE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Lipids
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/19/2014
Publication Date: 4/25/2014
Citation: Spartano, N.L., Lamon-Fava, S., Matthan, N.R., Obin, M.S., Greenberg, A.S., Lichtenstein, A.H. 2014. Linoleic acid suppresses cholesterol efflux and ATP-binding cassette transporters in murine bone marrow-derived macrophages. Lipids. 49(5):415-422.

Interpretive Summary: Individuals with type 2 diabetes mellitus are at increased risk of developing heart disease, possibly associated with elevated free fatty acid concentrations in their blood. Paradoxically, evidence suggests that unsaturated, compared to saturated fatty acids, suppress macrophage cholesterol efflux, favoring cholesterol accumulation in the artery wall and the development of heart disease. Mouse bone marrow-derived macrophages (BMDM) were used to explore the relationship between saturated and unsaturated fatty acids, and cholesterol efflux mediated cholesterol transporters through transcription factors liver-x-receptor-alpha (LXR-alpha) and sterol receptor element binding protein (SREBP)-1. BMDM were isolated and exposed to linoleic acid, an unsaturated fatty acid or palmitic acid, a saturated fatty acid, and oxidized low density lipoprotein, a source of cholesterol. Cholesterol transporter gene expression was suppressed to a greater extent by linoleic acid than palmitic acid relative to control treated cells. Linoleic acid decreased the transporter protein levels and high density lipoprotein (HDL) mediated cholesterol efflux, but had no significant effect on cholesterol transporters, LXR-alpha or SREBP-1 protein levels. Palmitic acid had no effect on cholesterol transporter, LXR-a and SREBP-1 protein expression or cellular cholesterol efflux to HDL. These results suggest that linoleic acid, relative to palmitic acid, lessened macrophage HDL-mediated cholesterol efflux through down regulation of cholesterol transporter mRNA and protein levels but not through changes in the transcription factors LXR-alpha or SREBP-1 expression. The effect of linoleic acid relative to palmitic acid on macrophages cholesterol homeostasis may exacerbate the predisposition of individuals with type 2 diabetes mellitus to increased heart disease risk.

Technical Abstract: Individuals with type 2 diabetes mellitus (T2DM) are at increased risk of developing cardiovascular disease (CVD), possibly associated with elevated plasma free fatty acid concentrations. Paradoxically, evidence suggests that unsaturated, compared to saturated fatty acids, suppress macrophage cholesterol efflux, favoring cholesterol accumulation in the artery wall. Murine bone marrow-derived macrophages (BMDM) were used to further explore the relationship between saturated and unsaturated fatty acids, and cholesterol efflux mediated by ATP-binding cassette transporters (ABCA1 and ABCG1) through transcription factors liver-x-receptor-alpha (LXR-Alpha) and sterol receptor element binding protein (SREBP)-1. BMDM isolated from C57BL/6 mice were exposed to 100 uM linoleic acid (18:2) or palmitic acid (16:0) for 16 hr, and 25 ug/mL oxidized low density lipoprotein for an additional 24 hr. ABCA1 and ABCG1 mRNA expression was suppressed to a greater extent by 18:2 (60% and 54 %, respectively) than 16:0 (30% and 29%, respectively) relative to control (all p<0.01). 18:2 decreased ABCA1 protein levels by 94% and high density lipoprotein (HDL) mediated cholesterol efflux by 53% (both p<0.05), and had no significant effect on ABCG1, LXR-a or SREBP-1 protein levels. 16:0 had no effect on ABCA1, ABCG1, LXR-Alpha or SREBP-1 protein expression or HDL-mediated cholesterol efflux. These results suggest that 18:2, relative to 16:0, attenuated macrophage HDL-mediated cholesterol efflux through down regulation of ABCA1 mRNA and protein levels but not through changes in LXR-Alpha or SREBP-1 expression. The effect of 18:2 relative to 16:0 on macrophages cholesterol homeostasis may exacerbate the predisposition of individuals with T2DM to increased CVD risk.