Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system.
Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system.
复制标题
DOI：
10.1016/j.tiv.2016.11.014
复制
发表时间：
2017-03
影响因子：
3.2
通讯作者：
Wamhoff, B. R.
中科院分区：
文献类型：
--
作者：
Dash, A.;Figler, R. A.;Blackman, B. R.;Marukian, S.;Collado, M. S.;Lawson, M. J.;Hoang, S. A.;Mackey, A. J.;Manka, D.;Cole, B. K.;Feaver, R. E.;Sanyal, A. J.;Wamhoff, B. R.
非酒精性脂肪性肝炎(NASH)是一种新兴的健康危机，目前还没有得到批准的治疗方法。乙酰胆酸(OCA)是一种法尼类X受体(FXR)激动剂，在NASH试验中显示出良好的前景。然而，OCA对胆固醇代谢的作用和影响的确切机制还不完全清楚。我们探索了OCA对肝细胞病理生理途径的药物毒理作用，使用了前面描述的灌流器官型肝脏系统，该系统允许在近生理的胰岛素/葡萄糖环境中培养，并在临床相关浓度下显示药物反应。原代肝细胞在接近治疗性(0.5μM)和超治疗性(10μM)水平的浓度下暴露48小时。通过细胞存活率、细胞色素P450活性测定和培养上清液中FGF19的分泌水平来评价RNAseq的整体转录水平。剂量依赖的转录效应表明胆汁酸的合成(↓细胞色素P7A1，↓细胞色素P27A1)受到抑制，而胆汁外流增加(↑ABCB4，↑ABCB11，↑OSTA，↑OSTB)。多效性作用包括抑制转化生长因子β和IL-6信号通路，以及高密度脂蛋白抑制信号(↑SCARB1、↓载脂蛋白AI、↓LCAT)和低密度脂蛋白升高(↑载脂蛋白B、↓细胞色素P7A1)。OCA表现出FXR介导的直接作用，增加FGF19的分泌。转录学揭示了对NASH有益的代谢、抗炎和抗纤维化途径的调节，并预测了与临床结果一致的胆固醇谱。在脂毒性/炎症条件下的后续研究将在与疾病相关的环境中证实这些影响。
Nonalcoholic steatohepatitis (NASH) is an emerging health crisis with no approved therapies. Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, shows promise in NASH trials. However, the precise mechanisms mediating OCA effects and impact on cholesterol metabolism are not fully understood. We explored the pharmaco-toxicological effects of OCA on pathophysiological pathways in hepatocytes using a previously described perfused organotypic liver system that allows culture in near-physiological insulin/glucose milieus, and exhibits drug responses at clinically-relevant concentrations. Primary hepatocytes experienced 48 -hour exposure to OCA at concentrations approximating therapeutic (0.5μM) and supratherapeutic (10μM) levels. Global transcriptomics by RNAseq was complimented by cellular viability (MTT), CYP activity assays, and secreted FGF19 levels in the media. Dose-dependent, transcriptional effects suggested suppression of bile acid synthesis (↓CYP7A1, ↓CYP27A1) and increased bile efflux (↑ABCB4, ↑ABCB11, ↑OSTA, ↑OSTB). Pleiotropic effects included suppression of TGFβ and IL-6 signaling pathways, and signatures suggestive of HDL suppression (↑SCARB1, ↓ApoAI, ↓LCAT) and LDL elevation (↑ApoB, ↓CYP7A1). OCA exhibited direct FXR-mediated effects with increased FGF19 secretion. Transcriptomics revealed regulation of metabolic, anti-inflammatory, and anti-fibrotic pathways beneficial in NASH, and predicted cholesterol profiles consistent with clinical findings. Follow-up studies under lipotoxic/inflammatory conditions would corroborate these effects in a disease-relevant environment.
登录
查看更多内容
DOI：
10.1093/bioinformatics/btq033
发表时间：
2010-03-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Quinlan AR;Hall IM
通讯作者：
Hall IM
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
DOI：
10.1016/j.apsb.2015.01.004
发表时间：
2015-03
期刊：
Acta pharmaceutica Sinica. B
影响因子：
--
作者：
Ding L;Yang L;Wang Z;Huang W
通讯作者：
Huang W
影响因子：
29.4
作者：
Mudaliar, Sunder;Henry, Robert R.;Shapiro, David
通讯作者：
Shapiro, David
影响因子：
--
作者：
Neupert, D;Glöckner, R;Müller, D
通讯作者：
Müller, D