Experimental non-alcoholic fatty liver disease results in decreased hepatic uptake transporter expression and function in rats.
Experimental non-alcoholic fatty liver disease results in decreased hepatic uptake transporter expression and function in rats.
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DOI：
10.1016/j.ejphar.2009.04.002
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发表时间：
2009-06-24
影响因子：
5
通讯作者：
Cherrington NJ
中科院分区：
文献类型：
--
作者：
Fisher CD;Lickteig AJ;Augustine LM;Oude Elferink RP;Besselsen DG;Erickson RP;Cherrington NJ
非酒精性脂肪性肝病（NAFLD）包括从单纯性脂肪肝（SFL）到非酒精性脂肪性肝炎（NASH）的一系列诊断。本研究旨在确定中度和重度NAFLD对体内肝脏转运蛋白表达和功能的影响。大鼠喂食高脂肪饮食（SFL模型）或蛋氨酸胆碱缺乏饮食（NASH模型）8周。肝摄取转运蛋白功能测定溴磺酞（BSP）处置。通过分支DNA信号放大试验和蛋白质印迹法测定转运蛋白表达;通过肝切片白细胞介素1 β（IL-1β）免疫染色鉴定炎症。与对照组大鼠相比，MC-大鼠血浆中BSP的保留显著。与对照组相比，高脂和MC饮食大鼠的肝脏NTCP、OATP 1a 1、1a 4、1b 2和2b 1以及OAT 2和3 mRNA水平显著降低。与对照组相比，高脂动物中OATP 1a 1的蛋白表达显著降低，而MC-大鼠中OATP 1a 1和OATP 1b 2的表达显著降低。高脂和MC-大鼠的肝组织对IL-1β染色呈阳性，IL-1β是一种已知可降低NTCP、OATP和OAT转运蛋白表达的促炎细胞因子，表明观察到的转运蛋白改变的合理机制。这些数据表明，NAFLD的不同阶段导致肝脏摄取转运蛋白表达改变，这可能导致从血液中摄取异生物质的功能受损。此外，NAFLD可能改变依赖于这些转运蛋白的临床相关药物的血浆保留时间，并可能增加潜在的药物毒性。
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of diagnoses ranging from simple fatty liver (SFL), to non-alcoholic steatohepatitis (NASH). This study aimed to determine the effect of moderate and severe NAFLD on hepatic transporter expression and function in vivo. Rats were fed a high-fat diet (SFL model) or a methionine-choline-deficient diet (NASH model) for eight weeks. Hepatic uptake transporter function was determined by bromosulfophthalein (BSP) disposition. Transporter expression was determined by branched DNA signal amplification assay and western blotting; inflammation was identified by immunostaining of liver slices for interleukin 1 beta (IL-1β). MC- rats showed significant retention of BSP in the plasma when compared to control rats. Hepatic NTCP, OATP1a1, 1a4, 1b2 and 2b1; and OAT 2 and 3 mRNA levels were significantly decreased in high-fat and MC- diet rats when compared to control. Protein expression of OATP1a1 was significantly decreased in high-fat animals, while OATP1a1 and OATP1b2 expression was significantly lower in MC- rats when compared to control. Liver tissue from high-fat and MC- rats stained positive for IL-1β, a pro-inflammatory cytokine known to decrease expression of NTCP, OATP and OAT transporters, suggesting a plausible mechanism for the observed transporter alterations. These data suggest that different stages of NAFLD result in altered hepatic uptake transporter expression that can lead to a functional impairment of xenobiotic uptake from the blood. Furthermore, NAFLD may alter the plasma retention time of clinically relevant drugs that are reliant on these transporters and may increase the potential drug toxicity.
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影响因子：
25.7
作者：
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通讯作者：
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影响因子：
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作者：
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作者：
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DOI：
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发表时间：
2005-08-22
影响因子：
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作者：
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