小柯机器人

荷兰皇家艺术与科学学院Hans Clevers，Benedetta Artegiani和Delilah Hendriks共同合作，近期取得重要工作进展。他们研究开发出工程化人类肝细胞类器官，使基于CRISPR的脂肪变性靶点发现和药物筛选成为可能。相关研究成果2023年2月23日在线发表于《自然—生物技术》杂志上。

据介绍，非酒精性脂肪肝（NAFLD）缺乏注册药物的部分原因是缺乏用于靶点发现和化合物筛选的人类相关模型。

研究人员使用人类胎儿肝细胞类器官来模拟NAFLD的第一阶段，脂肪变性，代表三种不同的触发因素：游离脂肪酸负荷、个体间遗传变异性（PNPLA3 I148M）和单基因脂质紊乱（APOB和MTTP突变）。候选药物的筛选揭示了有效解决脂肪变性的化合物。有效药物的机制评估揭示了作为收敛分子途径的从头脂肪生成的抑制。研究人员提出了FatTracer，一种CRISPR筛选平台，用于使用APOB^−/−和MTTP^−/−类器官识别脂肪变性调节剂和假定的靶点。通过筛选35个与脂质代谢或NAFLD风险相关的基因，研究人员发现，FADS2（脂肪酸去饱和酶 2）是肝脏脂肪变性的重要决定因素。FADS2表达的增强增加了多不饱和脂肪酸的丰度，进而减少了新的脂肪生成。

总之，这些类器官模型有助于脂肪变性病因和药物靶点的研究。

附：英文原文

Title: Engineered human hepatocyte organoids enable CRISPR-based target discovery and drug screening for steatosis

Author: Hendriks, Delilah, Brouwers, Jos F., Hamer, Karien, Geurts, Maarten H., Luciana, La, Massalini, Simone, Lpez-Iglesias, Carmen, Peters, Peter J., Rodrguez-Colman, Maria J., Chuva de Sousa Lopes, Susana, Artegiani, Benedetta, Clevers, Hans

Issue&Volume: 2023-02-23

Abstract: The lack of registered drugs for nonalcoholic fatty liver disease (NAFLD) is partly due to the paucity of human-relevant models for target discovery and compound screening. Here we use human fetal hepatocyte organoids to model the first stage of NAFLD, steatosis, representing three different triggers: free fatty acid loading, interindividual genetic variability (PNPLA3 I148M) and monogenic lipid disorders (APOB and MTTP mutations). Screening of drug candidates revealed compounds effective at resolving steatosis. Mechanistic evaluation of effective drugs uncovered repression of de novo lipogenesis as the convergent molecular pathway. We present FatTracer, a CRISPR screening platform to identify steatosis modulators and putative targets using APOB/ and MTTP/ organoids. From a screen targeting 35genes implicated in lipid metabolism and/or NAFLD risk, FADS2 (fatty acid desaturase2) emerged as an important determinant of hepatic steatosis. Enhancement of FADS2 expression increases polyunsaturated fatty acid abundancy which, in turn, reduces de novo lipogenesis. These organoid models facilitate study of steatosis etiology and drug targets.

DOI: 10.1038/s41587-023-01680-4

Source: https://www.nature.com/articles/s41587-023-01680-4

Nature Biotechnology：《自然—生物技术》，创刊于1996年。隶属于施普林格·自然出版集团，最新IF：68.164
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