Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom.
PLoS One. 2013 May 2;8(5):e62934. doi: 10.1371/journal.pone.0062934. Print 2013.
Nicotinic acid (NA) regresses atherosclerosis in human imaging studies and reduces atherosclerosis in mice, mediated by myeloid cells, independent of lipoproteins. Since GPR109A is expressed by human monocytes, we hypothesized that NA may drive cholesterol efflux from foam cells. In THP-1 cells NA suppressed LPS-induced mRNA transcription of MCP-1 by 76.6±12.2% (P<0.01) and TNFα by 56.1±11.5% (P<0.01), yet restored LPS-induced suppression of PPARγ transcription by 536.5±46.4% (P<0.001) and its downstream effector CD36 by 116.8±19.8% (P<0.01). Whilst direct PPARγ-agonism promoted cholesterol efflux from THP-1 derived foam cells by 37.7±3.1% (P<0.01) and stimulated transcription of LXRα by 87.9±9.5% (P<0.001) and ABCG1 by 101.2±15.5% (P<0.01), NA showed no effect in foam cells on either cholesterol efflux or key RCT genes transcription. Upon foam cell induction, NA lost its effect on PPARγ and cAMP pathways, since its receptor, GPR109A, was down-regulated by foam cell transformation. This observation was confirmed in explanted human carotid plaques. In conclusion, despite NA's anti-inflammatory effect on human macrophages, it has no effect on foam cells in reverse cholesterol transport; due to GPR109A down-regulation.
烟酸（NA）可在人体影像学研究中使动脉粥样硬化消退，并通过髓样细胞减少小鼠的动脉粥样硬化，这与脂蛋白无关。由于 GPR109A 在人单核细胞中表达，我们假设 NA 可能会促进泡沫细胞中的胆固醇外流。在 THP-1 细胞中，NA 抑制 LPS 诱导的单核细胞趋化蛋白-1（MCP-1）mRNA 转录 76.6±12.2%（P<0.01）和 TNFα 转录 56.1±11.5%（P<0.01），但恢复了 LPS 诱导的 PPARγ 转录抑制 536.5±46.4%（P<0.001）及其下游效应物 CD36 转录 116.8±19.8%（P<0.01）。虽然直接的 PPARγ 激动剂可使 THP-1 衍生的泡沫细胞中的胆固醇外流增加 37.7±3.1%（P<0.01），并刺激 LXRα 转录增加 87.9±9.5%（P<0.001）和 ABCG1 转录增加 101.2±15.5%（P<0.01），但 NA 在泡沫细胞中对胆固醇外流或关键 RCT 基因转录均无影响。在泡沫细胞诱导后，NA 丧失了对 PPARγ 和 cAMP 途径的作用，因为其受体 GPR109A 被泡沫细胞转化下调。这一观察结果在离体人颈动脉斑块中得到了证实。总之，尽管 NA 对人巨噬细胞具有抗炎作用，但由于 GPR109A 下调，它对胆固醇逆转运中的泡沫细胞没有影响。
