Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
Medical Scientist Training Program, Medical University of South Carolina, Charleston, SC 29425, USA.
Int J Mol Sci. 2024 Jul 2;25(13):7277. doi: 10.3390/ijms25137277.
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 and -induced pluripotent stem cells (iPSCs). Lipid levels were measured by staining with BODIPY 493/503 and were found to increase in 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.
非酒精性脂肪性肝病（NAFLD）或代谢相关脂肪性肝病（MAFLD）的发病率在成年人和儿童中都在增加。遗憾的是，目前仍然缺乏有效的药物治疗方法。在疾病进展的各个阶段，载脂蛋白样磷脂酶域蛋白 3（PNPLA3）基因中的单核苷酸多态性（SNP）与该疾病的相关性最为显著。阻碍发现针对 PNPLA3 诱导的非酒精性脂肪性肝病的潜在治疗方法的一个障碍是缺乏能够重现 PNPLA3 I148M 介导的脂质积累起始的人类细胞平台。本研究从诱导多能干细胞（iPSC）中生成了肝样细胞。通过用 BODIPY 493/503 染色测量脂质水平，发现 变体 iPSC 衍生的肝细胞中的脂质水平增加。通过小分子筛选鉴定出多种靶向Src/PI3K/Akt 信号通路的化合物，这些化合物可消除这些细胞中的脂质积累。研究发现，目前用于癌症治疗的针对相同通路的药物也可减少 PNPLA3 变体细胞中的脂质积累。
