Undifferentiated Induced Pluripotent Stem Cells as a Genetic Model for Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in the United States. NAFLD is initiated when excess fat builds up in the liver (a state called hepatic steatosis). An individual's risk of developing NAFLD is attributed, in part, to genetic factors. Patient-derived induced pluripotent stem cells (iPSCs) are cell lines generated from specific individuals that can be used to model the effects of human genetic variation. For studies of NAFLD, to study a more physiologically relevant cell type, iPSCs are typically differentiated into liver-like cells. However, this process is both time intensive and expensive, limiting the number of cell lines that can be studied. Here we evaluate whether iPSCs in their undifferentiated state can be used to assess the impact of NAFLD genetic risk on the accumulation of fat within the cells (aka cellular steatosis). Using iPSCs from 30 different donors, we found that these cell lines can accumulate fat like liver-derived cells, and that the magnitude of the cellular steatosis varies across cell Ines from different individuals. Importantly, iPSCs from donors with high NAFLD genetic risk had greater cellular steatosis than cell lines from donors with low NAFLD genetic risk. These findings suggest that undifferentiated iPSCs can be used in the study of NAFLD genetics to test the function of gene variants associated with NAFLD, or to identify new gene variants that cause NAFLD. In addition, this study demonstrates the potential importance of iPSCs themselves as a model system that can be used to define individual level disease risk.