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Palmitic acid enhances lectin-like oxidized LDL receptor (LOX-1) expression and promotes uptake of oxidized LDL in macrophage cells. 2010

Junichi Ishiyama, and Ryoko Taguchi, and Akiko Yamamoto, and Koji Murakami
Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., Shimotsuga-gun, Tochigi, Japan.

OBJECTIVE Elevated levels of nonesterified fatty acids (NEFA) in obesity and type 2 diabetes may contribute to the development of atherosclerosis. Therefore, we examined whether NEFA could regulate expression of scavenger receptors responsible for uptake of oxidized LDL (oxLDL) in macrophages, a critical step in atherogenesis. RESULTS Expression level of scavenger receptors in NEFA-treated macrophage-like THP-1 and Raw264.7 cells were analyzed by real-time PCR. Palmitic acid showed the greatest enhancement of expression of lectin-like oxidized LDL receptor (LOX-1) among 7 NEFA examined (4 saturated and 3 unsaturated fatty acids). Upregulation of LOX-1 was selective as increases in expression level of other scavenger receptors (CD36, SR-AI, SR-BI, and CD68) were not observed. Western blotting analysis indicated that upregulation of LOX-1 also occurred at the protein level. Uptake of oxLDL by Raw264.7 cells was promoted by palmitic acid, and the enhanced uptake was abrogated when the cells were transfected with siRNA against LOX-1. Downregulation of Toll-like receptor (TLR) 2, TLR4, or IRAK4 with siRNA did not prevent LOX-1 upregulation, whereas inhibitors of p38 MAPK (p38) and reactive oxygen species (ROS) signal inhibited the upregulation of LOX-1 induced by palmitic acid. CONCLUSIONS These results suggest that elevated level of palmitic acid may contribute to development of atherosclerosis through enhanced uptake of oxLDL via upregulation of LOX-1 in macrophages. The effects of palmitic acid may be mediated by ROS-p38 pathway rather than TLRs.

UI MeSH Term Description Entries
D008077 Lipoproteins, LDL A class of lipoproteins of small size (18-25 nm) and light (1.019-1.063 g/ml) particles with a core composed mainly of CHOLESTEROL ESTERS and smaller amounts of TRIGLYCERIDES. The surface monolayer consists mostly of PHOSPHOLIPIDS, a single copy of APOLIPOPROTEIN B-100, and free cholesterol molecules. The main LDL function is to transport cholesterol and cholesterol esters to extrahepatic tissues. Low-Density Lipoprotein,Low-Density Lipoproteins,beta-Lipoprotein,beta-Lipoproteins,LDL(1),LDL(2),LDL-1,LDL-2,LDL1,LDL2,Low-Density Lipoprotein 1,Low-Density Lipoprotein 2,LDL Lipoproteins,Lipoprotein, Low-Density,Lipoproteins, Low-Density,Low Density Lipoprotein,Low Density Lipoprotein 1,Low Density Lipoprotein 2,Low Density Lipoproteins,beta Lipoprotein,beta Lipoproteins
D008264 Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood MONOCYTES. Main types are PERITONEAL MACROPHAGES; ALVEOLAR MACROPHAGES; HISTIOCYTES; KUPFFER CELLS of the liver; and OSTEOCLASTS. They may further differentiate within chronic inflammatory lesions to EPITHELIOID CELLS or may fuse to form FOREIGN BODY GIANT CELLS or LANGHANS GIANT CELLS. (from The Dictionary of Cell Biology, Lackie and Dow, 3rd ed.) Bone Marrow-Derived Macrophages,Monocyte-Derived Macrophages,Macrophage,Macrophages, Monocyte-Derived,Bone Marrow Derived Macrophages,Bone Marrow-Derived Macrophage,Macrophage, Bone Marrow-Derived,Macrophage, Monocyte-Derived,Macrophages, Bone Marrow-Derived,Macrophages, Monocyte Derived,Monocyte Derived Macrophages,Monocyte-Derived Macrophage
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015536 Down-Regulation A negative regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (GENE EXPRESSION REGULATION), mRNAs (RNA, MESSENGER), and proteins. Receptor Down-Regulation,Down-Regulation (Physiology),Downregulation,Down Regulation,Down-Regulation, Receptor
D017382 Reactive Oxygen Species Molecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include SINGLET OXYGEN; SUPEROXIDES; PEROXIDES; HYDROXYL RADICAL; and HYPOCHLOROUS ACID. They contribute to the microbicidal activity of PHAGOCYTES, regulation of SIGNAL TRANSDUCTION and GENE EXPRESSION, and the oxidative damage to NUCLEIC ACIDS; PROTEINS; and LIPIDS. Active Oxygen Species,Oxygen Radical,Oxygen Radicals,Pro-Oxidant,Reactive Oxygen Intermediates,Active Oxygen,Oxygen Species, Reactive,Pro-Oxidants,Oxygen, Active,Pro Oxidant,Pro Oxidants,Radical, Oxygen
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines
D048051 p38 Mitogen-Activated Protein Kinases A mitogen-activated protein kinase subfamily that regulates a variety of cellular processes including CELL GROWTH PROCESSES; CELL DIFFERENTIATION; APOPTOSIS; and cellular responses to INFLAMMATION. The P38 MAP kinases are regulated by CYTOKINE RECEPTORS and can be activated in response to bacterial pathogens. Mitogen-Activated Protein Kinase p38,p38 Mitogen-Activated Protein Kinase,p38 MAP Kinase,p38 MAPK,p38 Protein Kinase,p38 SAPK,MAP Kinase, p38,MAPK, p38,Mitogen Activated Protein Kinase p38,Protein Kinase, p38,p38 Mitogen Activated Protein Kinase,p38 Mitogen Activated Protein Kinases
D050197 Atherosclerosis A thickening and loss of elasticity of the walls of ARTERIES that occurs with formation of ATHEROSCLEROTIC PLAQUES within the ARTERIAL INTIMA. Atherogenesis,Atherogeneses,Atheroscleroses
D051127 Scavenger Receptors, Class E A class of oxidized LDL receptors that contain C-type lectin-like extracellular domains. Scavenger Receptors, Class E, Type I,Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1,OLR1 Protein,Oxidized Low-Density Lipoprotein Receptor 1,SR-E Proteins,SR-EI Proteins,Lectin Like Oxidized Low Density Lipoprotein Receptor 1,Oxidized Low Density Lipoprotein Receptor 1,SR EI Proteins

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