Niacin induces PPARγ expression and transcriptional activation in macrophages via HM74 and HM74a-mediated induction of prostaglandin synthesis pathways
Niacin induces PPARγ expression and transcriptional activation in macrophages via HM74 and HM74a-mediated induction of prostaglandin synthesis pathways
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DOI：
10.1016/j.bcp.2005.11.019
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发表时间：
2006-02-28
影响因子：
5.8
通讯作者：
Harris, AL
中科院分区：
文献类型：
--
作者：
Knowles, HJ;Poole, RT;Harris, AL
HM74和HM74a是烟酸的受体。HM74a通过减少细胞内环磷酸腺苷(CAMP)和抑制游离脂肪酸的释放来介导烟酸在脂肪细胞中的药理抗脂作用。在巨噬细胞中，烟酸诱导依赖于PPARγ和cAMP依赖的介导胆固醇反向转运的基因的表达，尽管是通过一个未知的受体。我们描述了HM74a mRNA的组成性表达，以及缺氧和干扰素γ诱导的HM74和HM74a在培养的人单核细胞系和原代细胞中的表达。在烟酸诱导的U937细胞中，15-脱氧-Delta(12，14)-前列腺素J(2)(15d-PGJ(2))是PPAR-γ最有效的内源性配体。烟酸和结构不同的HM74/HM74a配体acifran均可诱导PPARγ蛋白的核表达，并增强PPARγ的转录活性。烟酸诱导的PPARγ转录活性是百日咳毒素敏感的，需要磷脂酶A(2)(EC 3.1.1.4)、环氧合酶(EC 1.14.99.1)和前列腺素D-2合成酶(EC 5.3.99.2)的活性。烟酸还能诱导HM74和HM74a CHO细胞中的PPARγ转录活性，但不能在仅携带载体的对照细胞中诱导。该菌对百日咳毒素、磷脂酶A(2)和环氧合酶活性的抑制敏感。此外，烟酸通过百日咳毒素和环氧合酶敏感机制增加U937细胞内cAMP。这些结果表明，HM74和HM74a可能通过激活前列腺素合成途径和诱导和激活PPAR-γ来介导巨噬细胞对烟酸的反应。这提示了一种新的调节药理剂量烟酸临床效应的机制(S)。(C)2005 Elsevier Inc.保留所有权利。
HM74 and HM74a have been identified as receptors for niacin. HM74a mediates the pharmacological anti-lipolytic effects of niacin in adipocytes by reducing intracellular cyclic AMP (cAMP) and inhibiting release of free fatty acids into the circulation. In macrophages, niacin induces peroxisome proliferator-activated receptor gamma (PPAR gamma)-dependent and cAMP-dependent expression of genes mediating reverse cholesterol transport, although via an unidentified receptor. We describe constitutive expression of HM74a mRNA and hypoxia-and IFN gamma-inducible expression of HM74 and HM74a in human monocytic cell lines and primary cells in culture. In U937 cells niacin-induced expression of 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), the most potent endogenous ligand of PPAR gamma. Both niacin and the structurally distinct HM74/HM74a ligand acifran-induced nuclear expression of PPAR gamma protein and enhanced PPAR gamma transcriptional activity. Niacin-induced PPAR gamma transcriptional activity was pertussis toxin sensitive and required activity of phospholipase A(2) (EC 3.1.1.4), cyclo-oxygenase (EC 1.14.99.1) and prostaglandin D-2 synthase (EC 5.3.99.2). Niacin also induced PPAR gamma transcriptional activity in HM74 and HM74a CHO cell transfectants, although not in vector-only control cells. This was sensitive to pertussis toxin and to inhibition of phoshoplipase A(2) and cyclo-oxygenase activity. Additionally, niacin increased intracellular cAMP in U937 via a pertussis toxin and cyclo-oxygenase-sensitive mechanism. These results indicate that HM74 and HM74a can mediate macrophage responses to niacin via activation of the prostaglandin synthesis pathway and induction and activation of PPAR gamma. This suggests a novel mechanism(s) mediating the clinical effects of pharmacological doses of niacin. (c) 2005 Elsevier Inc. All rights reserved.