Pluripotent Stem Cell-Derived Hepatocytes Phenotypic Screening Reveals Small Molecules Targeting the CDK2/4-C/EBPα/DGAT2 Pathway Preventing ER-Stress Induced Lipid Accumulation.
Pluripotent Stem Cell-Derived Hepatocytes Phenotypic Screening Reveals Small Molecules Targeting the CDK2/4-C/EBPα/DGAT2 Pathway Preventing ER-Stress Induced Lipid Accumulation.
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DOI：
10.3390/ijms21249557
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发表时间：
2020-12-15
影响因子：
5.6
通讯作者：
Malany S
中科院分区：
文献类型：
--
作者：
Parafati M;Bae SH;Kirby RJ;Fitzek M;Iyer P;Engkvist O;Smith DM;Malany S
非酒精性脂肪肝（NAFLD）对全球健康有很大影响。在疾病发作时，NAFLD的特征在于肝脂肪变性，其定义为储存为脂滴的甘油三酯的积累。开发针对NAFLD和进展为非酒精性脂肪性肝炎（NASH）的治疗方法仍然是医学和科学界的高度优先事项。用于鉴定潜在治疗化合物的药物发现计划支持体外人类相关NAFLD模型的高通量/高内容筛选，以加速有效抗脂肪变性药物的开发。人类诱导多能干细胞（hiPSC）技术是用于疾病建模和基于细胞的治疗和个性化医学的治疗评估的强大平台。在这项研究中，我们应用阿斯利康的化学基因组文库，hiPSC技术和多重高含量筛选来鉴定显着降低细胞内中性脂质含量的化合物。在筛选的13，000种化合物中，我们确定了通过作用机制（包括抑制细胞周期蛋白D3-细胞周期蛋白依赖性激酶2 - 4（CDK 2 - 4）/CCAAT增强子结合蛋白（C/EBP α）/二酰基甘油酰基转移酶2（DGAT 2）途径，然后改变与NAFLD相关的下游基因的表达）保护hiPSC源性肝内质网应激诱导的脂肪变性的命中物。这些发现表明，我们的表型平台为药物发现提供了可靠的方法，以确定治疗脂肪肝疾病的新药并阐明其潜在机制。
Non-alcoholic fatty liver disease (NAFLD) has a large impact on global health. At the onset of disease, NAFLD is characterized by hepatic steatosis defined by the accumulation of triglycerides stored as lipid droplets. Developing therapeutics against NAFLD and progression to non-alcoholic steatohepatitis (NASH) remains a high priority in the medical and scientific community. Drug discovery programs to identify potential therapeutic compounds have supported high throughput/high-content screening of in vitro human-relevant models of NAFLD to accelerate development of efficacious anti-steatotic medicines. Human induced pluripotent stem cell (hiPSC) technology is a powerful platform for disease modeling and therapeutic assessment for cell-based therapy and personalized medicine. In this study, we applied AstraZeneca’s chemogenomic library, hiPSC technology and multiplexed high content screening to identify compounds that significantly reduced intracellular neutral lipid content. Among 13,000 compounds screened, we identified hits that protect against hiPSC-derived hepatic endoplasmic reticulum stress-induced steatosis by a mechanism of action including inhibition of the cyclin D3-cyclin-dependent kinase 2-4 (CDK2-4)/CCAAT-enhancer-binding proteins (C/EBPα)/diacylglycerol acyltransferase 2 (DGAT2) pathway, followed by alteration of the expression of downstream genes related to NAFLD. These findings demonstrate that our phenotypic platform provides a reliable approach in drug discovery, to identify novel drugs for treatment of fatty liver disease as well as to elucidate their underlying mechanisms.
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