Differential modulation of rat hepatic stellate phenotype by natural and synthetic retinoids
Differential modulation of rat hepatic stellate phenotype by natural and synthetic retinoids
复制标题
DOI：
10.1002/hep.20015
复制
发表时间：
2004-01-01
期刊：
影响因子：
13.5
通讯作者：
Geerts, A
中科院分区：
文献类型：
--
作者：
Hellemams, K;Verbuyst, P;Geerts, A
肝星状细胞(HSC)的激活是慢性肝损伤肝纤维化发病机制中的中心事件。我们检测了维甲酸(RAR)和维甲酸X受体(RXR)在HSC激活过程中的表达，并评价了天然和合成维甲酸(RA)对培养激活的HSC表型的影响。Northern杂交分析主要RAR/RXR亚型和亚型的表达。凝胶位移分析证实存在功能性受体蛋白。应用视黄酸、RAR和RXR选择性激动剂以及一种RAR拮抗剂，通过Northern印迹和免疫沉淀法评价维甲酸信号对基质合成的影响，并通过BrdU掺入来评价视黄酸信号对细胞增殖的影响。9-Cisra和合成的RXR激动剂减少了HSC的增殖和I型胶原和纤维连接蛋白的合成。全反式RA和RAR激动剂均可减少I型胶原、III型胶原和纤维连接蛋白的合成，但对细胞增殖的影响不同。合成的RAR激动剂不影响HSC的增殖，表明ATRA抑制细胞生长不依赖于其与RAR的相互作用。相反，RAR特异性拮抗剂促进HSC的增殖，并证明RAR以负向方式控制HSC的增殖。综上所述，天然RAS和合成RAR或RXR特异性配体对活化的HSC有不同的作用。我们的观察可能解释了先前在培养的星状细胞或受到纤维化刺激的动物中应用维甲酸后获得的不同结果。
Activation of hepatic stellate cells (HSC) is a central event in the pathogenesis of liver fibrosis during chronic liver injury. We examined the expression of retinoic acid (RAR) and retinoid X receptors (RXR) during HSC activation and evaluated the influence of natural and synthetic retinoic acids (RA) on the phenotype of culture-activated HSC. The expression of the major RAR/RXR subtypes and isoforms was analyzed by Northern hybridization. Presence of functional receptor proteins was established by gel shift analysis. Retinoic acids, RAR, and RXR selective agonists and an RAR antagonist were used to evaluate the effects of retinoid signalling on matrix synthesis by Northern blotting and immunoprecipitation, and on cell proliferation by BrdU incorporation. The 9-cisRA and synthetic RXR agonists reduced HSC proliferation and synthesis of collagen I and fibronectin. All-trans RA and RAR agonists both reduced the synthesis of collagen I, collagen III, and fibronectin, but showed a different effect on cell proliferation. Synthetic RAR agonists did not affect HSC proliferation, indicating that ATRA inhibits cell growth independent of its interaction with RARs. In contrast, RAR specific antagonists enhance HSC proliferation and demonstrate that RARs control proliferation in a negative way. In conclusion, natural RAs and synthetic RAR or RXR specific ligands exert differential effects on activated HSC. Our observations may explain prior divergent results obtained following retinoid administration to cultured stellate cells or to animals subjected to fibrogenic stimuli.