Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., Shimotsuga-gun, Tochigi, Japan.
Atherosclerosis. 2010 Mar;209(1):118-24. doi: 10.1016/j.atherosclerosis.2009.09.004. Epub 2009 Sep 9.
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.
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.
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.
肥胖症和 2 型糖尿病患者体内非酯化脂肪酸（NEFA）水平升高，可能导致动脉粥样硬化的发生。因此，我们研究了 NEFA 是否可以调节巨噬细胞中氧化型 LDL（oxLDL）摄取相关清道夫受体的表达，这是动脉粥样硬化形成的关键步骤。
通过实时 PCR 分析 NEFA 处理的巨噬细胞样 THP-1 和 Raw264.7 细胞中清道夫受体的表达水平。在所研究的 7 种 NEFA 中，棕榈酸（7 种饱和和不饱和脂肪酸中的 4 种）对凝集素样氧化型 LDL 受体（LOX-1）的表达增强作用最大。LOX-1 的上调具有选择性，因为其他清道夫受体（CD36、SR-AI、SR-BI 和 CD68）的表达水平没有增加。Western blot 分析表明，LOX-1 的表达也在蛋白水平上上调。棕榈酸促进了 Raw264.7 细胞对 oxLDL 的摄取，当用 LOX-1 的 siRNA 转染细胞时，增强的摄取被阻断。用 siRNA 下调 Toll 样受体（TLR）2、TLR4 或 IRAK4 并不能阻止 LOX-1 的上调，而 p38 MAPK（p38）和活性氧（ROS）信号抑制剂则抑制了棕榈酸诱导的 LOX-1 上调。
这些结果表明，高水平的棕榈酸可能通过上调巨噬细胞中 LOX-1 来促进 oxLDL 的摄取，从而导致动脉粥样硬化的发生。棕榈酸的作用可能是通过 ROS-p38 途径介导的，而不是 TLRs。
