Department of Medicine, University of Washington, Seattle, Washington, USA.
Diabetes. 2010 Feb;59(2):386-96. doi: 10.2337/db09-0925. Epub 2009 Nov 23.
Obesity is associated with monocyte-macrophage accumulation in adipose tissue. Previously, we showed that glucose-stimulated production by adipocytes of serum amyloid A (SAA), monocyte chemoattractant protein (MCP)-1, and hyaluronan (HA) facilitated monocyte accumulation. The current objective was to determine how the other major nutrient, free fatty acids (FFAs), affects these molecules and monocyte recruitment by adipocytes.
Differentiated 3T3-L1, Simpson-Golabi-Behmel syndrome adipocytes, and mouse embryonic fibroblasts were exposed to various FFAs (250 micromol/l) in either 5 or 25 mmol/l (high) glucose for evaluation of SAA, MCP-1, and HA regulation in vitro.
Saturated fatty acids (SFAs) such as laurate, myristate, and palmitate increased cellular triglyceride accumulation, SAA, and MCP-1 expression; generated reactive oxygen species (ROS); and increased nuclear factor (NF) kappaB translocation in both 5 and 25 mmol/l glucose. Conversely, polyunsaturated fatty acids (PUFAs) such as arachidonate, eicosapentaenate, and docosahexaenate (DHA) decreased these events. Gene expression could be dissociated from triglyceride accumulation. Although excess glucose increased HA content, SFAs, oleate, and linoleate did not. Antioxidant treatment repressed glucose- and palmitate-stimulated ROS generation and NFkappaB translocation and decreased SAA and MCP-1 expression and monocyte chemotaxis. Silencing toll-like receptor-4 (TLR4) markedly reduced SAA and MCP-1 expression in response to palmitate but not glucose. DHA suppressed NFkappaB translocation stimulated by both excess glucose and palmitate via a peroxisome prolifterator-activated receptor (PPAR) gamma-dependent pathway.
Excess glucose and SFAs regulate chemotactic factor expression by a mechanism that involves ROS generation, NFkappaB, and PPARgamma, and which is repressed by PUFAs. Certain SFAs, but not excess glucose, trigger chemotactic factor expression via a TLR4-dependent pathway.
肥胖与脂肪组织中单核细胞-巨噬细胞的积聚有关。此前，我们发现葡萄糖刺激脂肪细胞产生血清淀粉样蛋白 A（SAA）、单核细胞趋化蛋白 1（MCP-1）和透明质酸（HA），促进单核细胞的积聚。本研究旨在确定另一种主要营养素——游离脂肪酸（FFAs）如何影响这些分子以及脂肪细胞对单核细胞的募集。
分化的 3T3-L1、Simpson-Golabi-Behmel 综合征脂肪细胞和小鼠胚胎成纤维细胞在 5 或 25mmol/L（高）葡萄糖中暴露于各种 FFAs（250μmol/L），以评估体外 SAA、MCP-1 和 HA 的调节。
饱和脂肪酸（SFAs）如月桂酸、肉豆蔻酸和棕榈酸增加细胞内甘油三酯的积累、SAA 和 MCP-1 的表达；产生活性氧（ROS）；并增加 NFkappaB 在 5 和 25mmol/L 葡萄糖中的易位。相反，多不饱和脂肪酸（PUFAs）如花生四烯酸、二十碳五烯酸和二十二碳六烯酸（DHA）则减少了这些事件。基因表达可以与甘油三酯的积累分离。尽管过多的葡萄糖增加了 HA 的含量，但 SFAs、油酸和亚油酸却没有。抗氧化剂处理抑制了葡萄糖和棕榈酸盐刺激的 ROS 生成和 NFkappaB 易位，并降低了 SAA 和 MCP-1 的表达和单核细胞趋化性。沉默 toll 样受体-4（TLR4）显著减少了对棕榈酸盐的反应，但不是葡萄糖的 SAA 和 MCP-1 的表达。DHA 通过过氧化物酶体增殖物激活受体（PPAR）γ依赖性途径抑制由过量葡萄糖和棕榈酸盐刺激的 NFkappaB 易位。
过量的葡萄糖和 SFAs 通过涉及 ROS 生成、NFkappaB 和 PPARgamma 的机制调节趋化因子的表达，而这些机制被 PUFAs 所抑制。某些 SFAs，但不是过量的葡萄糖，通过 TLR4 依赖的途径触发趋化因子的表达。
