PDF(Pubmed)
Abstract：
The incidence of nonalcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated fatty liver disease (MAFLD), is increasing in adults and children. Unfortunately, effective pharmacological treatments remain unavailable. Single nucleotide polymorphisms (SNPs) in the patatin-like phospholipase domain-containing protein (PNPLA3 I148M) have the most significant genetic association with the disease at all stages of its progression. A roadblock to identifying potential treatments for PNPLA3-induced NAFLD is the lack of a human cell platform that recapitulates the PNPLA3 I148M-mediated onset of lipid accumulation. Hepatocyte-like cells were generated from PNPLA3-/- and PNPLA3I148M/M-induced pluripotent stem cells (iPSCs). Lipid levels were measured by staining with BODIPY 493/503 and were found to increase in PNPLA3 variant iPSC-derived hepatocytes. A small-molecule screen identified multiple compounds that target Src/PI3K/Akt signaling and could eradicate lipid accumulation in these cells. We found that drugs currently in clinical trials for cancer treatment that target the same pathways also reduced lipid accumulation in PNPLA3 variant cells.
摘要：
非酒精性脂肪性肝病（NAFLD）的发病率，或代谢功能障碍相关的脂肪肝疾病（MAFLD），在成人和儿童中正在增加。不幸的是,有效的药物治疗仍然不可用。含patatin类磷脂酶结构域的蛋白质（PNPLA3I148M）中的单核苷酸多态性（SNP）在疾病进展的所有阶段与疾病具有最重要的遗传关联。确定PNPLA3诱导的NAFLD的潜在治疗方法的障碍是缺乏概括PNPLA3I148M介导的脂质积累开始的人细胞平台。从PNPLA3-/-和PNPLA3I148M/M诱导的多能干细胞(iPSC)产生肝细胞样细胞。通过用BODIPY493/503染色测量脂质水平,发现在PNPLA3变体iPSC衍生的肝细胞中增加。小分子筛选鉴定了靶向Src/PI3K/Akt信号传导并且可以根除这些细胞中的脂质积累的多种化合物。我们发现，目前在临床试验中针对相同途径的癌症治疗药物也减少了PNPLA3变异细胞中的脂质积累。
