Palmitic acid enhances lectin-like oxidized LDL receptor (LOX-1) expression and promotes uptake of oxidized LDL in macrophage cells.
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.
Ishiyama
Junichi
J
Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., Shimotsuga-gun, Tochigi, Japan.
Taguchi
Ryoko
R
Yamamoto
Akiko
A
Murakami
Koji
K
D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D019308:Palmitic Acid / Q000378:metabolism* / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000096:biosynthesis* / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C099252:oxidized low density lipoprotein; D019308:Palmitic Acid; D053592:Interleukin-1 Receptor-Associated Kinases; D048051:p38 Mitogen-Activated Protein Kinases