The TM6SF2 E167K genetic variant induces lipid biosynthesis and reduces apolipoprotein B secretion in human hepatic 3D spheroids
The TM6SF2 E167K genetic variant induces lipid biosynthesis and reduces apolipoprotein B secretion in human hepatic 3D spheroids
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DOI：
10.1038/s41598-019-47737-w
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发表时间：
2019-08-12
影响因子：
4.6
通讯作者：
Romeo, Stefano
中科院分区：
文献类型：
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作者：
Prill, Sebastian;Caddeo, Andrea;Romeo, Stefano
对于开发非酒精性脂肪性肝病（NAFLD）的治疗方法存在高度未满足的需求，目前还没有批准的药物。在这里，我们使用人类体外疾病模型来了解与NAFLD相关的遗传风险变异相关的机制。该模型基于来自五个不同供体的原代人肝细胞的3D球体。在这些供体中，我们观察到脂肪变性诱导程度的高度可重复性差异，表明供体间变异性反映在体外模型中。重要的是，我们的数据表明，以前与NAFLD风险增加相关的遗传变异TM6SF2 E167 K通过减少APOB颗粒分泌诱导肝细胞脂肪含量增加。最后，在体外模型中证实了野生型和TM6SF2 E167K突变携带者（N = 125）之间涉及胆固醇、脂肪酸和葡萄糖代谢的基因表达途径的差异。我们的数据表明，3D体外球状体可用于研究与NAFLD相关的人类遗传变异的相关机制。该模型也可能适合于发现针对NAFLD的新治疗方法。
There is a high unmet need for developing treatments for nonalcoholic fatty liver disease (NAFLD), for which there are no approved drugs today. Here, we used a human in vitro disease model to understand mechanisms linked to genetic risk variants associated with NAFLD. The model is based on 3D spheroids from primary human hepatocytes from five different donors. Across these donors, we observed highly reproducible differences in the extent of steatosis induction, demonstrating that inter-donor variability is reflected in the in vitro model. Importantly, our data indicates that the genetic variant TM6SF2 E167K, previously associated with increased risk for NAFLD, induces increased hepatocyte fat content by reducing APOB particle secretion. Finally, differences in gene expression pathways involved in cholesterol, fatty acid and glucose metabolism between wild type and TM6SF2 E167K mutation carriers (N = 125) were confirmed in the in vitro model. Our data suggest that the 3D in vitro spheroids can be used to investigate the mechanisms underlying the association of human genetic variants associated with NAFLD. This model may also be suitable to discover new treatments against NAFLD.