title: Linoleic acid suppresses cholesterol efflux and ATP-binding cassette transporters in murine bone marrow-derived macrophages.
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-α) and sterol receptor element binding protein (SREBP)-1. BMDM isolated from C57BL/6 mice were exposed to 100 μM linoleic acid (18:2) or palmitic acid (16:0) for 16 h, and 25 μg/mL oxidized low density lipoprotein for an additional 24 h. 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 the 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-α or SREBP-1 protein levels. 16:0 had no effect on ABCA1, ABCG1, LXR-α 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-α 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.
authors.affiliation: J. M. USDA Human Nutrition Research Center on Aging, Tufts University, 711 Washington Street, Boston, MA, USA, 02111, nicole.spartano@tufts.edu.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Spartano
authors.forename: Stefania
authors.initials: S
authors.lastname: Lamon-Fava
authors.forename: Nirupa R
authors.initials: NR
authors.lastname: Matthan
authors.forename: Martin S
authors.initials: MS
authors.lastname: Obin
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Greenberg
authors.forename: Alice H
authors.initials: AH
authors.lastname: Lichtenstein
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D002784:Cholesterol / Q000378:metabolism*; D019787:Linoleic Acid / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013329:Structure-Activity Relationship
chemical_list: D018528:ATP-Binding Cassette Transporters; D002784:Cholesterol; D019787:Linoleic Acid