Department of Biochemistry and Molecular Biology, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates.
Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates.
Cell Death Dis. 2022 Aug 1;13(8):670. doi: 10.1038/s41419-022-05125-9.
Obesity is a multigene disorder. However, in addition to genetic factors, environmental determinants also participate in developing obesity and related pathologies. Thus, obesity could be best described as a combination of genetic and environmental perturbations often having its origin during the early developmental period. Environmental factors such as energy-dense food and sedentary lifestyle are known to be associated with obesogenicity. However, the combinatorial effects of gene-environment interactions are not well understood. Understanding the role of multiple genetic variations leading to subtle gene expression changes is not practically possible in monogenic or high-fat-fed animal models of obesity. In contrast, human induced pluripotent stem cells (hiPSCs) from individuals with familial obesity or an obesogenic genotype could serve as a good model system. Herein, we have used hiPSCs generated from normal and genetically obese subjects and differentiated them into hepatocytes in cell culture. We show that hepatocytes from obese iPSCs store more lipids and show increased cell death than normal iPSCs. Whole transcriptome analyses in both normal and obese iPSCs treated with palmitate compared to control revealed LXR-RXR and hepatic fibrosis pathways were enriched among other pathways in obese iPSCs compared to normal iPSCs. Among other genes, increased CD36 and CAV1 expression and decreased expression of CES1 in obese iPSCs could have been responsible for excess lipid accumulation, resulting in differential expression of genes associated with hepatic fibrosis, a key feature of non-alcoholic fatty liver disease (NAFLD). Our results demonstrate that iPSCs derived from genetically obese subjects could serve as an excellent model to understand the effects of this multigene disorder on organ development and may uncover pathologies of NAFLD, which is highly associated with obesity.
肥胖是一种多基因疾病。然而，除了遗传因素外，环境决定因素也参与了肥胖症和相关病理的发生。因此，肥胖症最好被描述为遗传和环境干扰的组合，这些干扰通常起源于早期发育阶段。已知高热量食物和久坐不动的生活方式等环境因素与肥胖有关。然而，基因-环境相互作用的组合效应尚未得到很好的理解。在单基因或高脂肪喂养的肥胖动物模型中，理解导致细微基因表达变化的多种遗传变异的作用在实践上是不可能的。相比之下，来自家族性肥胖或肥胖基因型个体的人诱导多能干细胞（hiPSC）可以作为一个很好的模型系统。在此，我们使用来自正常和遗传肥胖个体的 hiPSC 并在细胞培养中将其分化为肝细胞。我们表明，来自肥胖 hiPSC 的肝细胞储存更多的脂质，并且比正常 hiPSC 表现出更多的细胞死亡。与对照组相比，用棕榈酸处理的正常和肥胖 hiPSC 的全转录组分析显示，与正常 hiPSC 相比，肥胖 hiPSC 中 LXR-RXR 和肝纤维化途径以及其他途径更为丰富。在其他基因中，肥胖 hiPSC 中 CD36 和 CAV1 表达增加和 CES1 表达降低可能导致脂质过度积累，导致与肝纤维化相关的基因表达差异，肝纤维化是非酒精性脂肪性肝病（NAFLD）的一个关键特征。我们的结果表明，来自遗传肥胖个体的 hiPSC 可以作为一个很好的模型来理解这种多基因疾病对器官发育的影响，并可能揭示与肥胖高度相关的 NAFLD 的病理学。
