Effect of aminoguanidine on lipopolysaccharide-induced changes in rat liver transporters and transcription factors
Effect of aminoguanidine on lipopolysaccharide-induced changes in rat liver transporters and transcription factors
复制标题
DOI：
10.1248/bpb.31.412
复制
发表时间：
2008-03-01
影响因子：
2
通讯作者：
Sato, Hitoshi
中科院分区：
文献类型：
--
作者：
Aoki, Kimiko;Nakajima, Miki;Sato, Hitoshi
为探讨一氧化氮(NO)在大鼠肝脏转运蛋白调节中的作用，我们用诱导型一氧化氮合酶(INOS)抑制剂氨基胍(AG)研究了NO是否介导了脂多糖(LPS)诱导的转运蛋白及其转录因子表达的变化。我们证实，在给药后16h，脂多糖降低了Ntcp、Oatp1、Oatp2、Oatp4、Oct1、mrp2、mdr1a的mRNA水平，而增加了mdr1b的mRNA水平。AG可减轻Ntcp、Oatp1和Oatp4(视黄醇X受体(RXR)α和肝细胞核因子(HNF)4α依赖基因)的表达下降，以及Mdr1b(核因子(NF)-kappa B依赖基因)的表达增加。同时，它还抑制内毒素诱导的NF-kappa B依赖的基因转录，如促炎症细胞因子(细胞因子；肿瘤坏死因子-α、白介素1-β、白介素6)和iNOS的转录，并在翻译后水平抑制枯否细胞(KCs)释放1L-1β，但对内毒素诱导的RXRα和HNF4α转录活性降低几乎没有影响。这些结果表明，肝细胞受到内毒素的直接刺激，导致核因子-kappaB的激活和RXRα和HNF4a转录活性的降低作为早期反应，而间接的细胞因子和NO通过激活核因子-kappaB从KCs释放作为延迟反应。结论：AG通过抑制肝细胞和KCs中NF-kappaB的活化，进而抑制KCs释放细胞因子和NO，从而减轻了LPS诱导的肝细胞Ntcp、Oatp1、Oatp4和Mdr1b转录的变化。然而，细胞因子和NO的作用无法区分。需要进一步的体外研究来阐明NO在转运蛋白调节中的作用。
To determine the role of nitric oxide (NO) in rat liver transporter regulation, we investigated whether NO mediates lipopolysaccharide (LPS)-induced changes in transporters and their transcription factor expression using aminoguanidine (AG), an inhibitor of induced nitric oxide synthase (iNOS). We confirmed that LPS decreased mRNA levels for Ntcp, Oatp1, Oatp2, Oatp4, Oct1, Mrp2, Mdr1a and increased those for Mdr1b at 16h after administration. AG attenuated these decreases for Ntcp, Oatp1 and Oatp4 (retinoid X receptor (RXR)alpha- and hepatocyte nuclear factor (HNF)4 alpha-dependent genes) and increase for Mdr1b (nuclear factor (NF)-kappa Bdependent gene). Concomitantly, it suppressed LPS-induced NF-kappa B-dependent gene transcription, such as those for proinflammatory cytokines (cytokines; tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-6) and iNOS, and also suppressed 1L-1 beta release from Kupffer cells (KCs) at post-translational levels, but had little effect on the LPS-induced decreases in RXR alpha and HNF4 alpha transcriptional activities. These findings indicate that hepatocytes were stimulated directly by LPS, which lead to the activation of NF-kappa B and reduction of RXR alpha and HNF4a transcriptional activities as early responses, and indirectly by cytokines and NO released from KCs via activation of NF-kappa B by LPS as delayed responses. We conclude that AG, which suppresses LPS-induced NF-kappa B activation in both hepatocytes and KCs and then the release of cytokines and NO from KCs, attenuates LPS-induced changes of Ntcp, Oatp1, Oatp4 and Mdr1b transcription in hepatocytes. The roles of cytokines and NO could not be distinguished, however. Further in vitro study is needed to clarify the role of NO in transporter regulation.