Sustained elevations in NEFA induce cyclooxygenase-2 activity and potentiate THP-1 macrophage foam cell formation

  • Eric E. Lloyd
    Section of Atherosclerosis and Lipoprotein Research, Department of Medicine, MS A-601, Baylor College of Medicine, 6565 Fannin St., Houston, TX 77030, United States
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  • John W. Gaubatz
    Section of Atherosclerosis and Lipoprotein Research, Department of Medicine, MS A-601, Baylor College of Medicine, 6565 Fannin St., Houston, TX 77030, United States
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  • Alan R. Burns
    Section of Cardiovascular Sciences, Department of Medicine, MS A-601, Baylor College of Medicine, 6565 Fannin St., Houston, TX 77030, United States
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  • Henry J. Pownall
    Corresponding author. Tel.: +1 713 798 4160; fax: +1 713 798 9005.
    Section of Atherosclerosis and Lipoprotein Research, Department of Medicine, MS A-601, Baylor College of Medicine, 6565 Fannin St., Houston, TX 77030, United States
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      Type 2 diabetes, a major risk factor for atherosclerosis, is associated with a cluster of lipid risk factors, many of which can be mechanistically linked with underlying dysregulated fatty acid metabolism and elevated plasma non-esterified fatty acids (NEFA). Thus, we tested the hypothesis that elevated NEFA dysregulates lipid metabolism at the levels of lipid synthesis and gene expression in THP-1 monocyte derived macrophages (MDM). THP-1 MDM incubated with oleic acid (OA) and a BODIPY-conjugated NEFA, accumulate, respectively, intracellular inclusions that are positive for oil red O and BODIPY-labeling. Parallel studies with [14C]OA show dose-dependent accumulation of intracellular 14C-labeled neutral lipid, almost exclusively as triglyceride; the rate of [3H]OA uptake increases as THP-1 MDM convert to foam cells. Preincubation of THP-1 MDM with higher concentrations of OA (1.8 mM versus 0.2 mM) was associated with enhanced uptake of Ac-LDL, and increased expression of adipocyte fatty acid binding protein, FAT/CD36, and cyclooxygenase-2 (COX-2); COX-2 mass and activity also increased. These observations suggest a mechanistic link between sustained elevations in albumin-bound NEFA and foam cell formation that may be mediated by enhanced adipogenesis, increased uptake of modified LDL, and upregulated formation of eicosanoids, which may be proinflammatory.


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