Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
Cell Signal. 2013 Oct;25(10):2003-16. doi: 10.1016/j.cellsig.2013.06.008. Epub 2013 Jun 14.
Until recently, the anti-atherosclerotic effects of niacin were attributed primarily to its lipid modification properties mediated by adipocyte G-protein coupled receptor GPR109A, though recent studies have raised significant doubts about this mechanism. In fact, in rodents it has recently been demonstrated that niacin inhibits progression of atherosclerosis through actions on immune cells, particularly via macrophage-expressed GPR109A, independent of lipid-modifying properties. Here, we studied GPR109A signal transduction in human Langerhans cells, macrophages and adipocytes. We find that the consequences of receptor activation are profoundly influenced by cellular context and that ligand-biased signaling significantly impacts functionally relevant signaling. In Langerhans cells, niacin initiates GPR109A-mediated signaling pathways (Erk1/2 and Ca(2+)) responsible for the release of vasodilatory prostanoids, while the synthetic GPR109A agonist MK-0354 fails to elicit any signaling, providing a mechanistic basis for the latter compound's inability to cause flushing. While GPR109A mediates inhibition of cAMP in adipocytes, in macrophages GPR109A signaling via Gβγ subunits results in paradoxical augmentation of intracellular cAMP levels. Also, in macrophages niacin and GPR109A full agonists induce Erk1/2 and Ca(2+) signaling, release of prostanoids, upregulation of cholesterol transporters ABCA1 and ABCG1 and stimulation of reverse cholesterol transport in GPR109A dependent manner. A mechanism is presented in which signals from the autocrine action of released prostanoids and Gi protein mediated cAMP augmentation are integrated leading to modulation of reverse cholesterol transport regulatory components. These studies provide key insights into mechanisms by which GPR109A may influence cholesterol efflux in macrophages; a process that may be at least partially responsible for niacin's anti-atherosclerotic activity. MK-0354 does not induce niacin-like GPR109A signaling in macrophages, suggesting that biased agonists devoid of the flushing side-effect may also lack properties required for macrophage-mediated anti-atherosclerotic effects.
直到最近，烟酸的抗动脉粥样硬化作用主要归因于其通过脂肪细胞 G 蛋白偶联受体 GPR109A 介导的脂质修饰特性，尽管最近的研究对这一机制提出了重大质疑。事实上，在啮齿动物中，最近已经证明烟酸通过作用于免疫细胞，特别是通过巨噬细胞表达的 GPR109A，抑制动脉粥样硬化的进展，而与脂质修饰特性无关。在这里，我们研究了 GPR109A 在人类朗格汉斯细胞、巨噬细胞和脂肪细胞中的信号转导。我们发现，受体激活的后果受到细胞环境的深刻影响，配体偏向信号显著影响功能相关信号。在朗格汉斯细胞中，烟酸启动 GPR109A 介导的信号通路（Erk1/2 和 Ca(2+)），负责释放血管舒张性前列腺素，而合成的 GPR109A 激动剂 MK-0354 不能引发任何信号，为后者化合物不能引起潮红提供了机制基础。虽然 GPR109A 在脂肪细胞中介导 cAMP 的抑制，但在巨噬细胞中，GPR109A 通过 Gβγ亚基的信号转导导致细胞内 cAMP 水平的反常增加。此外，在巨噬细胞中，烟酸和 GPR109A 完全激动剂诱导 Erk1/2 和 Ca(2+)信号转导、前列腺素释放、胆固醇转运体 ABCA1 和 ABCG1 的上调以及 GPR109A 依赖性的胆固醇逆向转运的刺激。提出了一种机制，其中自分泌作用释放的前列腺素和 Gi 蛋白介导的 cAMP 增加的信号被整合，导致调节胆固醇逆向转运的成分的调制。这些研究提供了关键的见解，了解 GPR109A 如何影响巨噬细胞中的胆固醇流出；这一过程可能至少部分负责烟酸的抗动脉粥样硬化活性。MK-0354 不会在巨噬细胞中诱导类似烟酸的 GPR109A 信号转导，表明缺乏潮红副作用的偏向激动剂可能也缺乏巨噬细胞介导的抗动脉粥样硬化作用所需的特性。
