Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages
Abstract Hepatic insulin resistance is recognized as a driver of type 2 diabetes and fatty liver disease but specific therapies are lacking. Here we explore the potential of human induced pluripotent stem cells (iPSCs) for modeling hepatic insulin resistance in vitro, with a focus on resolving the c...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39311-w |
| _version_ | 1797784516582965248 |
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| author | Marko Groeger Koji Matsuo Emad Heidary Arash Ashley Pereira Dounia Le Guillou Cindy Pino Kayque A. Telles-Silva Jacquelyn J. Maher Edward C. Hsiao Holger Willenbring |
| author_facet | Marko Groeger Koji Matsuo Emad Heidary Arash Ashley Pereira Dounia Le Guillou Cindy Pino Kayque A. Telles-Silva Jacquelyn J. Maher Edward C. Hsiao Holger Willenbring |
| author_sort | Marko Groeger |
| collection | DOAJ |
| description | Abstract Hepatic insulin resistance is recognized as a driver of type 2 diabetes and fatty liver disease but specific therapies are lacking. Here we explore the potential of human induced pluripotent stem cells (iPSCs) for modeling hepatic insulin resistance in vitro, with a focus on resolving the controversy about the impact of inflammation in the absence of steatosis. For this, we establish the complex insulin signaling cascade and the multiple inter-dependent functions constituting hepatic glucose metabolism in iPSC-derived hepatocytes (iPSC-Heps). Co-culture of these insulin-sensitive iPSC-Heps with isogenic iPSC-derived pro-inflammatory macrophages induces glucose output by preventing insulin from inhibiting gluconeogenesis and glycogenolysis and activating glycolysis. Screening identifies TNFα and IL1β as the mediators of insulin resistance in iPSC-Heps. Neutralizing these cytokines together restores insulin sensitivity in iPSC-Heps more effectively than individual inhibition, reflecting specific effects on insulin signaling and glucose metabolism mediated by NF-κB or JNK. These results show that inflammation is sufficient to induce hepatic insulin resistance and establish a human iPSC-based in vitro model to mechanistically dissect and therapeutically target this metabolic disease driver. |
| first_indexed | 2024-03-13T00:41:01Z |
| format | Article |
| id | doaj.art-ca63e7ea8e914071b9f2810f9b4f1a48 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T00:41:01Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-ca63e7ea8e914071b9f2810f9b4f1a482023-07-09T11:19:14ZengNature PortfolioNature Communications2041-17232023-07-0114111410.1038/s41467-023-39311-wModeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophagesMarko Groeger0Koji Matsuo1Emad Heidary Arash2Ashley Pereira3Dounia Le Guillou4Cindy Pino5Kayque A. Telles-Silva6Jacquelyn J. Maher7Edward C. Hsiao8Holger Willenbring9Division of Transplant Surgery, Department of Surgery, University of California San FranciscoDivision of Endocrinology and Metabolism, Department of Medicine, University of California San FranciscoDivision of Transplant Surgery, Department of Surgery, University of California San FranciscoDivision of Endocrinology and Metabolism, Department of Medicine, University of California San FranciscoDivision of Gastroenterology, Department of Medicine, University of California San FranciscoLiver Center, University of California San FranciscoEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San FranciscoDivision of Gastroenterology, Department of Medicine, University of California San FranciscoEli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San FranciscoDivision of Transplant Surgery, Department of Surgery, University of California San FranciscoAbstract Hepatic insulin resistance is recognized as a driver of type 2 diabetes and fatty liver disease but specific therapies are lacking. Here we explore the potential of human induced pluripotent stem cells (iPSCs) for modeling hepatic insulin resistance in vitro, with a focus on resolving the controversy about the impact of inflammation in the absence of steatosis. For this, we establish the complex insulin signaling cascade and the multiple inter-dependent functions constituting hepatic glucose metabolism in iPSC-derived hepatocytes (iPSC-Heps). Co-culture of these insulin-sensitive iPSC-Heps with isogenic iPSC-derived pro-inflammatory macrophages induces glucose output by preventing insulin from inhibiting gluconeogenesis and glycogenolysis and activating glycolysis. Screening identifies TNFα and IL1β as the mediators of insulin resistance in iPSC-Heps. Neutralizing these cytokines together restores insulin sensitivity in iPSC-Heps more effectively than individual inhibition, reflecting specific effects on insulin signaling and glucose metabolism mediated by NF-κB or JNK. These results show that inflammation is sufficient to induce hepatic insulin resistance and establish a human iPSC-based in vitro model to mechanistically dissect and therapeutically target this metabolic disease driver.https://doi.org/10.1038/s41467-023-39311-w |
| spellingShingle | Marko Groeger Koji Matsuo Emad Heidary Arash Ashley Pereira Dounia Le Guillou Cindy Pino Kayque A. Telles-Silva Jacquelyn J. Maher Edward C. Hsiao Holger Willenbring Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages Nature Communications |
| title | Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages |
| title_full | Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages |
| title_fullStr | Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages |
| title_full_unstemmed | Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages |
| title_short | Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages |
| title_sort | modeling and therapeutic targeting of inflammation induced hepatic insulin resistance using human ipsc derived hepatocytes and macrophages |
| url | https://doi.org/10.1038/s41467-023-39311-w |
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