Ke Liang-Yin, Chan Hua-Chen, Chan Hsiu-Chuan, Kalu Franklin Chikodi Udo, Lee Hsiang-Chun, Lin I-Ling, Jhuo Shih-Jie, Lai Wen-Ter, Tsao Chen-Rong, Sawamura Tatsuya, Dixon Richard A, Chen Chu-Huang, Chu Chih-Sheng, Shin Shyi-Jang
Vascular and Medicinal Research, Texas Heart Institute.
Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Taiwan.
J Clin Endocrinol Metab. 2017 Dec 1;102(12):4615-4625. doi: 10.1210/jc.2017-01657.
Electronegative low-density lipoprotein (LDL) L5 is a naturally occurring, atherogenic entity found at elevated levels in the plasma of patients with metabolic syndrome (MetS) in the absence of elevated plasma LDL levels.
To investigate the role of L5 in the mechanism of adipose tissue inflammation associated with MetS.
PATIENTS/SETTING: Plasma LDL isolated from patients with MetS (n = 29) and controls (n = 29) with similar plasma LDL levels was separated into five subfractions, L1 to L5, with increasing electronegativity.
We examined the invivo effects of L5 on adipose tissue in mice and the in vitro effects of L5 on adipocytokine signaling and monocytes.
Tail-vein injection of human L5 but not L1 into C57BL/6 mice induced the accumulation of F4/80+ and CD11c+ M1 macrophages. The effects of L5 were attenuated in mice deficient for L5's receptor, lectin-like oxidized LDL receptor 1 (LOX-1). L5 but not L1 induced human adipocytes to release inflammatory adipocytokines. Incubating human THP-1 monocytes with LDL-free culture media from L5-treated adipocytes enhanced the migration of monocytes by 300-fold (P < 0.001 vs L1-treated adipocyte media)-effects that were attenuated by LOX-1 neutralizing antibody. Migrated cells were positive for mature macrophage marker PM-2K, indicating the transformation of monocytes into macrophages. The infiltration of M1 macrophages in adipose tissue was also observed in a previously established hamster model of endogenously elevated L5.
L5 induces adipose inflammation through LOX-1 by promoting macrophage maturation and infiltration into adipose tissue. Elevated plasma L5 levels may be a novel etiology of adipose tissue inflammation in patients with MetS.
带负电的低密度脂蛋白（LDL）L5是一种天然存在的致动脉粥样硬化物质，在代谢综合征（MetS）患者血浆中水平升高，而此时血浆LDL水平并未升高。
研究L5在与MetS相关的脂肪组织炎症机制中的作用。
患者/研究环境：从血浆LDL水平相似的MetS患者（n = 29）和对照组（n = 29）中分离出的血浆LDL被分为五个亚组分，L1至L5，其负电性逐渐增强。
我们研究了L5对小鼠脂肪组织的体内作用以及L5对脂肪细胞因子信号传导和单核细胞的体外作用。
将人L5而非L1尾静脉注射到C57BL/6小鼠中可诱导F4/80+和CD11c+ M1巨噬细胞的积累。在缺乏L5受体（凝集素样氧化LDL受体1，LOX-1）的小鼠中，L5的作用减弱。L5而非L1可诱导人脂肪细胞释放炎性脂肪细胞因子。用来自L5处理的脂肪细胞的无LDL培养基孵育人THP-1单核细胞可使单核细胞的迁移增加300倍（与L1处理的脂肪细胞培养基相比，P < 0.001），这些作用被LOX-1中和抗体减弱。迁移的细胞对成熟巨噬细胞标志物PM-2K呈阳性，表明单核细胞转化为巨噬细胞。在先前建立的内源性L5升高的仓鼠模型中也观察到了M1巨噬细胞在脂肪组织中的浸润。
L5通过促进巨噬细胞成熟和浸润到脂肪组织中，经由LOX-1诱导脂肪炎症。血浆L5水平升高可能是MetS患者脂肪组织炎症的一种新病因。
