Feingold Kenneth R, Moser Arthur, Shigenaga Judy K, Grunfeld Carl
Metabolism Section, Department of Veterans Affairs Medical Center, University of California San Francisco, San Francisco, CA 94121.
J Lipid Res. 2014 Dec;55(12):2501-8. doi: 10.1194/jlr.M050955. Epub 2014 Oct 15.
Many of the beneficial and adverse effects of niacin are mediated via a G protein receptor, G protein-coupled receptor 109A/hydroxycarboxylic acid 2 receptor (GPR109A/HCA2), which is highly expressed in adipose tissue and macrophages. Here we demonstrate that immune activation increases GPR109A/HCA2 expression. Lipopolysaccharide (LPS), TNF, and interleukin (IL) 1 increase GPR109A/HCA2 expression 3- to 5-fold in adipose tissue. LPS also increased GPR109A/HCA2 mRNA levels 5.6-fold in spleen, a tissue rich in macrophages. In peritoneal macrophages and RAW cells, LPS increased GPR109A/HCA2 mRNA levels 20- to 80-fold. Zymosan, lipoteichoic acid, and polyinosine-polycytidylic acid, other Toll-like receptor activators, and TNF and IL-1 also increased GPR109A/HCA2 in macrophages. Inhibition of the myeloid differentiation factor 88 or TIR-domain-containing adaptor protein inducing IFNβ pathways both resulted in partial inhibition of LPS stimulation of GPR109A/HCA2, suggesting that LPS signals an increase in GPR109A/HCA2 expression by both pathways. Additionally, inhibition of NF-κB reduced the ability of LPS to increase GPR109A/HCA2 expression by ∼50% suggesting that both NF-κB and non-NF-κB pathways mediate the LPS effect. Finally, preventing the LPS-induced increase in GPR109A/HCA2 resulted in an increase in TG accumulation and the expression of enzymes that catalyze TG synthesis. These studies demonstrate that inflammation stimulates GPR109A/HCA2 and there are multiple intracellular signaling pathways that mediate this effect. The increase in GPR109A/HCA2 that accompanies macrophage activation inhibits the TG accumulation stimulated by macrophage activation.
烟酸的许多有益和不良作用是通过一种G蛋白受体，即G蛋白偶联受体109A/羟基羧酸2受体（GPR109A/HCA2）介导的，该受体在脂肪组织和巨噬细胞中高度表达。在此我们证明免疫激活会增加GPR109A/HCA2的表达。脂多糖（LPS）、肿瘤坏死因子（TNF）和白细胞介素（IL）-1可使脂肪组织中的GPR109A/HCA2表达增加3至5倍。LPS还使富含巨噬细胞的脾脏组织中的GPR109A/HCA2 mRNA水平增加5.6倍。在腹膜巨噬细胞和RAW细胞中，LPS使GPR109A/HCA2 mRNA水平增加20至80倍。其他Toll样受体激活剂，如酵母聚糖、脂磷壁酸和聚肌苷酸-聚胞苷酸，以及TNF和IL-1也会增加巨噬细胞中的GPR109A/HCA2。抑制髓样分化因子88或含TIR结构域的衔接蛋白诱导IFNβ途径均会部分抑制LPS对GPR109A/HCA2的刺激，这表明LPS通过这两条途径使GPR109A/HCA2表达增加。此外，抑制核因子κB（NF-κB）可使LPS增加GPR109A/HCA2表达的能力降低约50%，这表明NF-κB和非NF-κB途径均介导LPS的作用。最后，阻止LPS诱导的GPR109A/HCA2增加会导致甘油三酯（TG）积累增加以及催化TG合成的酶的表达增加。这些研究表明炎症会刺激GPR109A/HCA2，并且有多种细胞内信号通路介导这种作用。巨噬细胞激活伴随的GPR109A/HCA2增加会抑制巨噬细胞激活所刺激的TG积累。
