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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Peroxisome proliferator-activated receptor α activates human multidrug resistance transporter 3/ATP-binding cassette protein subfamily B4 transcription and increases rat biliary phosphatidylcholine secretion
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Peroxisome proliferator-activated receptor α activates human multidrug resistance transporter 3/ATP-binding cassette protein subfamily B4 transcription and increases rat biliary phosphatidylcholine secretion

机译：过氧化物酶体增殖物激活受体α激活人多药抗性转运蛋白3 / ATP结合盒蛋白亚家族B4转录并增加大鼠胆汁磷脂酰胆碱的分泌

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摘要

Multidrug resistance transporter 3/ATP-binding cassette protein subfamily B4 (MDR3/ABCB4) is a critical determinant of biliary phosphatidylcholine (PC) secretion. Clinically, mutations and partial deficiencies in MDR3 result in cholestatic liver injury. Thus, MDR3 is a potential therapeutic target for cholestatic liver disease. Fenofibrate is a peroxisome proliferator-activated receptor (PPAR) α ligand that has antiinflammatory actions and regulates bile acid detoxification. Here we examined the mechanism by which fenofibrate regulates MDR3 gene expression. Fenofibrate significantly up-regulated MDR3 messenger RNA (mRNA) and protein expression in primary cultured human hepatocytes, and stimulated MDR3 promoter activity in HepG2 cells. In silico analysis of 5′-upstream region of human MDR3 gene revealed a number of PPARα response elements (PPRE). Electrophoretic mobility shift (EMSA) and chromatin immunoprecipitation (ChIP) assays demonstrated specific binding of PPARα to the human MDR3 promoter. Targeted mutagenesis of three novel PPREs reduced inducibility of the MDR3 promoter by fenofibrate. In collagen sandwich cultured rat hepatocytes, treatment with fenofibrate increased secretion of fluorescent PC into bile canaliculi. Conclusion: Fenofibrate transactivates MDR3 gene transcription by way of the binding of PPARα to three novel and functionally critical PPREs in the MDR3 promoter. Fenofibrate treatment further stimulates biliary phosphatidylcholine secretion in rat hepatocytes, thereby providing a functional correlate. We have established a molecular mechanism that may contribute to the beneficial use of fenofibrate therapy in human cholestatic liver disease.
机译：多药耐药转运蛋白3 / ATP结合盒蛋白B4亚家族（MDR3 / ABCB4）是胆汁磷脂酰胆碱（PC）分泌的关键决定因素。临床上，MDR3的突变和部分缺陷会导致胆汁淤积性肝损伤。因此，MDR3是胆汁淤积性肝病的潜在治疗靶标。非诺贝特是一种过氧化物酶体增殖物激活受体（PPAR）α配体，具有抗炎作用并调节胆汁酸的解毒作用。在这里，我们检查了非诺贝特调节MDR3基因表达的机制。非诺贝特显着上调原代培养的人肝细胞中的MDR3信使RNA（mRNA）和蛋白表达，并刺激HepG2细胞中的MDR3启动子活性。在对人类MDR3基因5'上游区域的计算机分析中，发现了许多PPARα反应元件（PPRE）。电泳迁移率迁移（EMSA）和染色质免疫沉淀（ChIP）分析证明了PPARα与人MDR3启动子的特异性结合。三种新型PPRE的靶向诱变降低了非诺贝特对MDR3启动子的诱导性。在胶原蛋白夹心培养的大鼠肝细胞中，用非诺贝特治疗可增加荧光PC分泌到胆小管中。结论：非诺贝特通过PPARα与MDR3启动子中的三个新的和功能关键的PPRE结合而使MDR3基因转录反式激活。非诺贝特治疗进一步刺激大鼠肝细胞中胆汁磷脂酰胆碱的分泌，从而提供功能相关性。我们已经建立了一种分子机制，可能有助于非诺贝特疗法在人类胆汁淤积性肝病中的有益应用。

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