ABSTRACT
Consumption of trans fatty acids (TFA) increase cardiovascular risk more than do saturated FA, but the mechanisms explaining their atherogenicity are still unclear. We investigated the impact of membrane incorporation of TFA on cholesterol efflux by exposing J774 mouse macrophages or human monocyte-derived macrophages (HMDM) to media enriched or not (standard medium) with industrially produced elaidic (trans-9 18:1) acid, naturally produced vaccenic (trans-11 18:1) acid (34 h, 70 µM) or palmitic acid. In J774 macrophages, elaidic and palmitic acid, but not vaccenic acid, reduced ABCA1-mediated efflux by ~23% without affecting aqueous diffusion, SR-BI or ABCG1-mediated pathways, and this effect was maintained in cholesterol-loaded cells. The impact of elaidic acid on the ABCA1 pathway was weaker in cholesterol-normal HMDM, but elaidic acid induced a strong reduction of ABCA1-mediated efflux in cholesterol-loaded cells (-36%). In J774 cells, the FA supplies had no impact on cellular free cholesterol or cholesteryl ester masses, the abundance of ABCA1 mRNA or the total and plasma membrane ABCA1 protein content. Conversely, TFA or palmitic acid incorporation induced strong modifications of the membrane FA composition with a decrease in the ratio of (cis-monounsaturated FA+polyunsaturated FA):(saturated FA+TFA), with elaidic and vaccenic acids representing each 20% and 13% of the total FA composition, respectively. Moreover, we demonstrated that cellular ATP was required for the effect of elaidic acid, suggesting that it contributes to atherogenesis by impairing ABCA1-mediated cholesterol efflux in macrophages, likely by decreasing the membrane fluidity, which could thereby reduce ATPase activity and the function of the transporter.
Subject(s)
ATP-Binding Cassette Transporters/metabolism , Cholesterol/metabolism , Macrophages/drug effects , Macrophages/metabolism , Oleic Acid/pharmacology , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/genetics , Adenosine Triphosphate/metabolism , Animals , Biological Transport/drug effects , CD36 Antigens/metabolism , Cell Membrane/drug effects , Cell Membrane/metabolism , Diffusion/drug effects , Gene Expression Regulation/drug effects , Humans , Mice , Monocytes/cytology , Oleic Acids/pharmacology , Phospholipids/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
Since android overweight/obesity and insulin resistance are independent risk factors for cardiovascular disease, we investigated their impact on basal and postprandial scavenger receptor BI (SR-BI) and ATP binding cassette transporter A1 (ABCA1)-mediated serum cholesterol efflux. Twelve android overweight to obese and 9 normal weight controls women underwent body composition analysis by dual energy X-ray absorptiometry, a euglycemic hyperinsulinemic clamp, and an oral fat load with blood sampling at initial time (T0), 4h (T4) and 10h (T10) after the fat load. Serum lipids and HDL-parameters, capacities of serum to promote cholesterol efflux from SR-BI expressing Fu5AH hepatoma cells or from ABCA1-expressing J774 macrophages and to abilities of serum to induce a net removal of cholesterol from macrophage foam cells were measured at T0, T4 and T10. Sera from overweight/obese exhibited moderately decreased SR-BI-mediated cholesterol efflux capacities, in accordance with reduced HDL concentrations, but importantly increased ABCA1-mediated cholesterol efflux and increased cholesterol extraction capacities over the postprandial period, partly related to higher prebeta-HDL concentrations. In multiple regression analyses, android obesity-related parameters and HDL-PL or prebeta-HDL levels remained the only independent correlates for SR-BI or ABCA1-dependent fractional cholesterol efflux while only prebeta-HDL levels remained correlated to cholesterol extraction capacities. Our results suggest that android overweight/obesity may not result in an impaired cholesterol efflux capacity.
Subject(s)
ATP-Binding Cassette Transporters/blood , Cholesterol/blood , Insulin Resistance/physiology , Obesity/metabolism , Overweight/blood , Scavenger Receptors, Class B/blood , ATP Binding Cassette Transporter 1 , ATP Binding Cassette Transporter, Subfamily G, Member 1 , ATP-Binding Cassette Transporters/biosynthesis , Adult , Animals , Body Composition , Carcinoma, Hepatocellular/metabolism , Cell Line , Female , Foam Cells/metabolism , High-Density Lipoproteins, Pre-beta/physiology , Humans , Liver Neoplasms/metabolism , Macrophages/metabolism , Mice , Middle Aged , Postprandial Period , Rats , Tumor Cells, Cultured , Waist CircumferenceABSTRACT
Hypertriglyceridemia being an independent cardiovascular risk factor, we have compared the potential of sera from asymptomatic hypertriglyceridemic (HTG) type IIb, type IV or normolipidemic (NLP) subjects to promote both fractional cholesterol efflux and cellular cholesterol mass changes using macrophage foam cells. The J774 cells loaded with cholesterol by incubation with acetylated LDL were incubated in the absence or presence of cAMP to upregulate ABCA1 (ATP binding cassette transporter A1) and then incubated for 24h with 1% serum. Compared with NLP, type IV sera exhibited a major increase in ABCA1-dependent efflux while type IIb sera exhibited a moderate but not significant increased ABCA1-mediated efflux. Moreover, positive correlations were established between ABCA1-dependent efflux and the serum prebeta-HDL or TG concentrations. The major finding was that the sera from type IV induced higher total cholesterol and cholesteryl ester mass depletions from ABCA1-expressing cells compared with other groups. Moreover, negative correlations were obtained between total cholesterol or cholesteryl ester mass changes and serum prebeta-HDL levels. In conclusion, we demonstrated for the first time that the serum prebeta-HDL present in high proportions in type IV HTG subjects are not only responsible for higher cholesterol efflux potential but also for increased abilities to promote net removal of cholesterol from macrophage foam cells.
