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 35 genes implicated in lipid metabolism and/or NAFLD risk, FADS2 (fatty acid desaturase 2) 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.

缺乏治疗非酒精性脂肪性肝病（NAFLD）的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。在这里，我们使用人类胎儿肝细胞类器官来模拟 NAFLD 的第一阶段，即脂肪变性，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 (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可有效解决脂肪变性的化合物。对有效药物的机制评估发现，抑制从头脂肪生成是聚合分子途径。我们推出 FatTracer，这是一个 CRISPR 筛选平台，可使用APOB ^−/−和MTTP ^−/−类器官来识别脂肪变性调节剂和推定靶点。通过针对与脂质代谢和/或 NAFLD 风险相关的 35 个基因的筛选，FADS2（脂肪酸去饱和酶 2）成为肝脂肪变性的重要决定因素。 FADS2 表达的增强会增加多不饱和脂肪酸的丰度，从而减少脂肪从头生成。这些类器官模型有助于脂肪变性病因学和药物靶点的研究。