Sustained elevations in NEFA induce cyclooxygenase-2 activity and potentiate THP-1 macrophage foam cell formation.
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 [(14)C]OA show dose-dependent accumulation of intracellular (14)C-labeled neutral lipid, almost exclusively as triglyceride; the rate of [(3)H]OA uptake increases as THP-1 MDM convert to foam cells. Preincubation of THP-1 MDM with higher concentrations of OA (1.8mM versus 0.2mM) 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.
Lloyd
Eric E
EE
Section of Atherosclerosis and Lipoprotein Research, Department of Medicine, MS A-601, Baylor College of Medicine, 6565 Fannin St., Houston, TX 77030, United States.
Gaubatz
John W
JW
Burns
Alan R
AR
Pownall
Henry J
HJ
D017667:Adipocytes / Q000378:metabolism; D000418:Albumins / Q000378:metabolism; D018955:CD36 Antigens / Q000378:metabolism; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005487:Foam Cells / Q000502:physiology*; D020869:Gene Expression Profiling; D006801:Humans; D050356:Lipid Metabolism; D008264:Macrophages / Q000378:metabolism*; D008969:Molecular Sequence Data; D019301:Oleic Acid / Q000378:metabolism
D000418:Albumins; D018955:CD36 Antigens; D005230:Fatty Acids, Nonesterified; D019301:Oleic Acid; D051546:Cyclooxygenase 2