Loss of FOXA2 induces ER stress and hepatic steatosis and alters developmental gene expression in human iPSC-derived hepatocytes
Abstract FOXA2 has been known to play important roles in liver functions in rodents. However, its role in human hepatocytes is not fully understood. Recently, we generated FOXA2 mutant induced pluripotent stem cell (FOXA2−/−iPSC) lines and illustrated that loss of FOXA2 results in developmental defe...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05158-0 |
| _version_ | 1828434614751854592 |
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| author | Maryam Aghadi Ramy Elgendy Essam M. Abdelalim |
| author_facet | Maryam Aghadi Ramy Elgendy Essam M. Abdelalim |
| author_sort | Maryam Aghadi |
| collection | DOAJ |
| description | Abstract FOXA2 has been known to play important roles in liver functions in rodents. However, its role in human hepatocytes is not fully understood. Recently, we generated FOXA2 mutant induced pluripotent stem cell (FOXA2−/−iPSC) lines and illustrated that loss of FOXA2 results in developmental defects in pancreatic islet cells. Here, we used FOXA2−/−iPSC lines to understand the role of FOXA2 on the development and function of human hepatocytes. Lack of FOXA2 resulted in significant alterations in the expression of key developmental and functional genes in hepatic progenitors (HP) and mature hepatocytes (MH) as well as an increase in the expression of ER stress markers. Functional assays demonstrated an increase in lipid accumulation, bile acid synthesis and glycerol production, while a decrease in glucose uptake, glycogen storage, and Albumin secretion. RNA-sequencing analysis further validated the findings by showing a significant increase in genes associated with lipid metabolism, bile acid secretion, and suggested the activation of hepatic stellate cells and hepatic fibrosis in MH lacking FOXA2. Overexpression of FOXA2 reversed the defective phenotypes and improved hepatocyte functionality in iPSC-derived hepatic cells lacking FOXA2. These results highlight a potential role of FOXA2 in regulating human hepatic development and function and provide a human hepatocyte model, which can be used to identify novel therapeutic targets for FOXA2-associated liver disorders. |
| first_indexed | 2024-12-10T18:52:33Z |
| format | Article |
| id | doaj.art-6821a040cb8840ac87b974453f224384 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-10T18:52:33Z |
| publishDate | 2022-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-6821a040cb8840ac87b974453f2243842022-12-22T01:37:15ZengNature Publishing GroupCell Death and Disease2041-48892022-08-0113811410.1038/s41419-022-05158-0Loss of FOXA2 induces ER stress and hepatic steatosis and alters developmental gene expression in human iPSC-derived hepatocytesMaryam Aghadi0Ramy Elgendy1Essam M. Abdelalim2Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF)Discovery Biology, Discovery Sciences, R&D, AstraZenecaDiabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF)Abstract FOXA2 has been known to play important roles in liver functions in rodents. However, its role in human hepatocytes is not fully understood. Recently, we generated FOXA2 mutant induced pluripotent stem cell (FOXA2−/−iPSC) lines and illustrated that loss of FOXA2 results in developmental defects in pancreatic islet cells. Here, we used FOXA2−/−iPSC lines to understand the role of FOXA2 on the development and function of human hepatocytes. Lack of FOXA2 resulted in significant alterations in the expression of key developmental and functional genes in hepatic progenitors (HP) and mature hepatocytes (MH) as well as an increase in the expression of ER stress markers. Functional assays demonstrated an increase in lipid accumulation, bile acid synthesis and glycerol production, while a decrease in glucose uptake, glycogen storage, and Albumin secretion. RNA-sequencing analysis further validated the findings by showing a significant increase in genes associated with lipid metabolism, bile acid secretion, and suggested the activation of hepatic stellate cells and hepatic fibrosis in MH lacking FOXA2. Overexpression of FOXA2 reversed the defective phenotypes and improved hepatocyte functionality in iPSC-derived hepatic cells lacking FOXA2. These results highlight a potential role of FOXA2 in regulating human hepatic development and function and provide a human hepatocyte model, which can be used to identify novel therapeutic targets for FOXA2-associated liver disorders.https://doi.org/10.1038/s41419-022-05158-0 |
| spellingShingle | Maryam Aghadi Ramy Elgendy Essam M. Abdelalim Loss of FOXA2 induces ER stress and hepatic steatosis and alters developmental gene expression in human iPSC-derived hepatocytes Cell Death and Disease |
| title | Loss of FOXA2 induces ER stress and hepatic steatosis and alters developmental gene expression in human iPSC-derived hepatocytes |
| title_full | Loss of FOXA2 induces ER stress and hepatic steatosis and alters developmental gene expression in human iPSC-derived hepatocytes |
| title_fullStr | Loss of FOXA2 induces ER stress and hepatic steatosis and alters developmental gene expression in human iPSC-derived hepatocytes |
| title_full_unstemmed | Loss of FOXA2 induces ER stress and hepatic steatosis and alters developmental gene expression in human iPSC-derived hepatocytes |
| title_short | Loss of FOXA2 induces ER stress and hepatic steatosis and alters developmental gene expression in human iPSC-derived hepatocytes |
| title_sort | loss of foxa2 induces er stress and hepatic steatosis and alters developmental gene expression in human ipsc derived hepatocytes |
| url | https://doi.org/10.1038/s41419-022-05158-0 |
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