Nicotinic Acid Receptor GPR109A Is Down-Regulated in Human Macrophage-Derived Foam Cells

作者:Chai Joshua T; Digby Janet E; Ruparelia Neil; Jefferson Andrew; Handa Ashok; Choudhury Robin P*
来源:PLos One, 2013, 8(5): e62934.
DOI:10.1371/journal.pone.0062934

摘要

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 TNF alpha by 56.1 +/- 11.5% (P<0.01), yet restored LPS-induced suppression of PPAR gamma-transcription by 536.5 +/- 46.4% (P<0.001) and its downstream effector CD36 by 116.8 +/- 19.8% (P<0.01). Whilst direct PPAR gamma-agonism promoted cholesterol efflux from THP-1 derived foam cells by 37.7 +/- 3.1% (P<0.01) and stimulated transcription of LXR alpha 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 PPAR gamma 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.

  • 出版日期2013-5-2

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