The peroxisome proliferator-activated receptor δ promotes lipid accumulation in human macrophages
The peroxisome proliferator-activated receptor δ promotes lipid accumulation in human macrophages
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DOI：
10.1074/jbc.m108482200
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发表时间：
2001-11-23
影响因子：
4.8
通讯作者：
Palmer, CNA
中科院分区：
文献类型：
--
作者：
Vosper, H;Patel, L;Palmer, CNA
过氧化物酶体增殖物激活受体(PPAR)是一类由脂肪酸激活的转录因子家族，控制着脂质稳态和细胞分化。PPARα(NR1C1)控制肝细胞的脂质氧化和清除，PPARγ(NR1C3)促进前脂肪细胞分化和脂肪生成。激活PPARα的药物在降低血浆血脂水平方面有效，并已用于高脂血症的治疗。PPARγ激动剂可增加胰岛素敏感性，并用于2型糖尿病的治疗。相比之下，目前还没有针对PPAR Delta(NR1C2)的上市药物，而且PPAR Delta的生理作用尚不清楚。在这篇报道中，我们证明了PPAR5在人巨噬细胞体外分化过程中的表达增加。此外，PPAR Delta的高选择性激动剂(化合物F)促进原代人类巨噬细胞和来自人类单核细胞系THP-1的巨噬细胞的脂质积累。化合物F增加与脂质摄取和储存有关的基因的表达，如A和B类清道夫受体(SRA，CD36)和脂联素。PPAR Delta的激活也抑制了与脂质代谢和外流有关的关键基因，即。胆固醇27-羟基酶和载脂蛋白E。我们已经产生了高表达PPAR Delta的THP-1亚系，并证实PPAR Delta是巨噬细胞脂质堆积的强大促进剂。这些数据表明，PPAR5可能在与充满脂质的巨噬细胞相关的疾病的病理中发挥作用，如动脉粥样硬化、关节炎和神经退行性变。
The peroxisome Proliferator-activated receptors (PPARs) are a family of fatty acid-activated transcription factors which control lipid homeostasis and cellular differentiation. PPAR alpha (NR1C1) controls lipid oxidation and clearance in hepatocytes and PPAR gamma (NR1C3) promotes preadipocyte differentiation and lipogenesis. Drugs that activate PPAR alpha are effective in lowering plasma levels of lipids and have been used in the management of hyperlipidemia. PPAR gamma agonists increase insulin sensitivity and are used in the management of type 2 diabetes. In contrast, there are no marketed drugs that selectively target PPAR delta (NR1C2) and the physiological roles of PPAR delta are unclear. In this report we demonstrate that the expression of PPAR5 is increased during the differentiation of human macrophages in vitro. In addition, a highly selective agonist of PPAR delta (compound F) promotes lipid accumulation in primary human macrophages and in macrophages derived from the human monocytic cell line, THP-1. Compound F increases the expression of genes involved in lipid uptake and storage such as the class A and B scavenger receptors (SRA, CD36) and adipophilin. PPAR delta activation also represses key genes involved in lipid metabolism and efflux, ie. cholesterol 27-hydroxylase and apolipoprotein E. We have generated THP-1 sublines that overexpress PPAR delta and have confirmed that PPAR delta is a powerful promoter of macrophage lipid accumulation. These data suggest that PPAR5 may play a role in the pathology of diseases associated with lipid-filled macrophages, such as atherosclerosis, arthritis, and neurodegeneration.