Tumor necrosis factor α upregulates the bile acid efflux transporter OATP3A1 via multiple signaling pathways in cholestasis.
Tumor necrosis factor α upregulates the bile acid efflux transporter OATP3A1 via multiple signaling pathways in cholestasis.
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DOI：
10.1016/j.jbc.2021.101543
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Pan Q
中科院分区：
文献类型：
--
作者：
Li M;Wang W;Cheng Y;Zhang X;Zhao N;Tan Y;Xie Q;Chai J;Pan Q
胆汁淤积是一种常见的疾病，其中胆汁从肝脏到肠道的流动受到抑制。已经显示，有机阴离子转运多肽3A 1（OATP 3A 1）在胆汁淤积中上调以促进胆汁酸外排转运。我们之前已经证明，生长因子成纤维细胞生长因子19和炎症介质肿瘤坏死因子α（TNFα）增加了肝癌腹腔灌洗细胞/PRF/5细胞系中OATP 3A 1 mRNA的水平。然而，胆汁淤积中TNFα刺激OATP 3A 1表达的潜在机制尚不清楚。为了解决这个问题，我们收集了对照组和梗阻性胆汁淤积患者的血浆样本，并使用ELISA检测TNFα水平。我们发现阻塞性胆汁淤积患者血浆和肝脏mRNA转录的TNFα水平相对于对照组显著升高。阻塞性胆汁淤积患者血浆TNFα与肝脏OATP 3A 1 mRNA转录水平呈显著正相关。进一步的机制分析显示，重组TNFα诱导OATP 3A 1表达，激活NF-κB和细胞外信号调节激酶（ERK）信号通路，以及相关转录因子p65和特异性蛋白1（SP1）的表达。双荧光素酶报告基因和染色质免疫沉淀分析显示，重组TNFα可上调腹腔灌洗液细胞/PRF/5中NF-κB p65和SP 1与OATP 3A 1启动子的结合活性。在应用NF-κB和ERK抑制剂BAY 11 -7082和PD 98059后，这些作用减弱。我们得出结论，TNFα通过激活NF-κB p65和ERK-SP1信号通路刺激人阻塞性胆汁淤积症肝脏OATP 3A 1表达。这些结果表明，TNFα激活的NF-κB p65和ERK-SP1信号转导可能是改善胆汁淤积相关肝损伤的潜在靶点。
Cholestasis is a common condition in which the flow of bile from the liver to the intestines is inhibited. It has been shown that organic anion–transporting polypeptide 3A1 (OATP3A1) is upregulated in cholestasis to promote bile acid efflux transport. We have previously shown that the growth factor fibroblast growth factor 19 and inflammatory mediator tumor necrosis factor α (TNFα) increased OATP3A1 mRNA levels in hepatoma peritoneal lavage cell/PRF/5 cell lines. However, the mechanism underlying TNFα-stimulated OATP3A1 expression in cholestasis is unknown. To address this, we collected plasma samples from control and obstructive cholestasis patients and used ELISA to detect TNFα levels. We found that the TNFα levels of plasma and hepatic mRNA transcripts were significantly increased in obstructive cholestatic patients relative to control patients. A significant positive correlation was also observed between plasma TNFα and liver OATP3A1 mRNA transcripts in patients with obstructive cholestasis. Further mechanism analysis revealed that recombinant TNFα induced OATP3A1 expression and activated NF-κB and extracellular signal–regulated kinase (ERK) signaling pathways as well as expression of related transcription factors p65 and specificity protein 1 (SP1). Dual-luciferase reporter and chromatin immunoprecipitation assays showed that recombinant TNFα upregulated the binding activities of NF-κB p65 and SP1 to the OATP3A1 promoter in peritoneal lavage cell/PRF/5 cells. These effects were diminished following the application of NF-κB and ERK inhibitors BAY11-7082 and PD98059. We conclude that TNFα stimulates hepatic OATP3A1 expression in human obstructive cholestasis by activating NF-κB p65 and ERK–SP1 signaling. These results suggest that TNFα-activated NF-κB p65 and ERK–SP1 signaling may be a potential target to ameliorate cholestasis-associated liver injury.
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DOI：
10.1016/j.jbc.2021.100723
发表时间：
2021-01
期刊：
The Journal of biological chemistry
影响因子：
--
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