PPAR-γ dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation
PPAR-γ dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation
复制标题
DOI：
10.1038/83336
复制
发表时间：
2001-01-01
期刊：
影响因子：
82.9
通讯作者：
Evans, RM
中科院分区：
文献类型：
--
作者：
Chawla, A;Barak, Y;Evans, RM
过氧化物酶体增殖物激活受体-γ(PPAR-γ)在冠状动脉积脂巨噬细胞中高表达。有鉴于此，TZDS在治疗II型糖尿病中的广泛临床应用引起了人们对PPAR-γ在巨噬细胞功能和疾病进展中的作用的担忧。为了确定PPAR-Gamma在巨噬细胞生物学中的作用，我们使用同源重组创建了PPAR-Gamma基因零突变纯合的胚胎干细胞。我们在这里证明了PPAR-γ在体外和体内对巨噬细胞系的发育既不是必需的，也不是实质性的影响。相反，我们证明它是清道夫受体CD36的重要调节因子，CD36在基因上与巨噬细胞中的脂质积累有关。15-脱氧-三角洲(12，14)前列腺素J(2)和噻唑烷二酮类化合物都具有独立于PPAR-γ的抗炎作用。我们表明，PPAR-γ是其配体在调节巨噬细胞脂代谢中发挥积极作用所必需的，但对细胞因子产生和炎症的抑制作用可能不依赖于受体。
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is highly expressed in lipid-accumulating macrophages of the coronary artery. In light of this, the wide-spread clinical use of thiazolidinediones (TZDs) in the treatment of type II diabetes raises concerns about the role of PPAR-gamma in macrophage function and disease progression. To define the role of PPAR-gamma in macrophage biology, we used homologous recombination to create embryonic stem cells that were homozygous for a null mutation in the PPAR-gamma gene. We demonstrate here that PPAR-gamma is neither essential for nor substantially affects the development of the macrophage lineage both in vitro and in vivo. In contrast, we show it is an important regulator of the scavenger receptor CD36, which has been genetically linked to lipid accumulation in macrophages. Both 15-deoxy-Delta (12,14)prostaglandin J(2) and thiazolidinediones have anti-inflammatory effects that are independent of PPAR-gamma. We show that PPAR-gamma is required for positive effects of its ligands in modulating macrophage lipid metabolism, but that inhibitory effects on cytokine production and inflammation may be receptor independent.