Thyroid hormone receptor beta (THRβ1) is the major regulator of T3 action in human iPSC-derived hepatocytes
Objective: Thyroid hormone (TH) action is mediated by thyroid hormone receptor (THR) isoforms. While THRβ1 is likely the main isoform expressed in liver, its role in human hepatocytes is not fully understood. Methods: To elucidate the role of THRβ1 action in human hepatocytes we used CRISPR/Cas9 edi...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-12-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877824001881 |
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| author | Lorraine Soares De Oliveira Joseph E. Kaserman Anne H. Van Der Spek Nora J. Lee Hendrik J. Undeutsch Rhiannon B. Werder Andrew A. Wilson Anthony N. Hollenberg |
| author_facet | Lorraine Soares De Oliveira Joseph E. Kaserman Anne H. Van Der Spek Nora J. Lee Hendrik J. Undeutsch Rhiannon B. Werder Andrew A. Wilson Anthony N. Hollenberg |
| author_sort | Lorraine Soares De Oliveira |
| collection | DOAJ |
| description | Objective: Thyroid hormone (TH) action is mediated by thyroid hormone receptor (THR) isoforms. While THRβ1 is likely the main isoform expressed in liver, its role in human hepatocytes is not fully understood. Methods: To elucidate the role of THRβ1 action in human hepatocytes we used CRISPR/Cas9 editing to knock out THRβ1 in induced pluripotent stem cells (iPSC). Following directed differentiation to the hepatic lineage, iPSC-derived hepatocytes were then interrogated to determine the role of THRβ1 in ligand-independent and -dependent functions. Results: We found that the loss of THRβ1 promoted alterations in proliferation rate and metabolic pathways regulated by T3, including gluconeogenesis, lipid oxidation, fatty acid synthesis, and fatty acid uptake. We observed that key genes involved in liver metabolism are regulated through both T3 ligand-dependent and -independent THRβ1 signaling mechanisms. Finally, we demonstrate that following THRβ1 knockout, several key metabolic genes remain T3 responsive suggesting they are THRα targets. Conclusions: These results highlight that iPSC-derived hepatocytes are an effective platform to study mechanisms regulating TH signaling in human hepatocytes. |
| format | Article |
| id | doaj-art-f7b75a417d61423ebf131321c17d4271 |
| institution | Kabale University |
| issn | 2212-8778 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-f7b75a417d61423ebf131321c17d42712024-11-19T04:10:07ZengElsevierMolecular Metabolism2212-87782024-12-0190102057Thyroid hormone receptor beta (THRβ1) is the major regulator of T3 action in human iPSC-derived hepatocytesLorraine Soares De Oliveira0Joseph E. Kaserman1Anne H. Van Der Spek2Nora J. Lee3Hendrik J. Undeutsch4Rhiannon B. Werder5Andrew A. Wilson6Anthony N. Hollenberg7Department of Medicine, Section of Endocrinology, Diabetes and Nutrition, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, MA 02118, USA; Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USACenter for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USA; Department of Medicine, Section of Pulmonary and Critical Care Medicine, Chobanian & Avedisian School of Medicine, Boston Medical Center, MA 02118, USAAmsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam 1081 HV, NetherlandsCenter for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USADepartment of Medicine, Section of Endocrinology, Diabetes and Nutrition, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, MA 02118, USA; Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USACenter for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USACenter for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USA; Department of Medicine, Section of Pulmonary and Critical Care Medicine, Chobanian & Avedisian School of Medicine, Boston Medical Center, MA 02118, USA; Corresponding author. Department of Medicine, Section of Pulmonary and Critical Care Medicine, Chobanian & Avedisian School of Medicine, Boston Medical Center, MA 02118, USA.Department of Medicine, Section of Endocrinology, Diabetes and Nutrition, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, MA 02118, USA; Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, Boston, MA 02118, USA; Corresponding author. Department of Medicine, Section of Endocrinology, Diabetes and Nutrition, Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, MA 02118, USA.Objective: Thyroid hormone (TH) action is mediated by thyroid hormone receptor (THR) isoforms. While THRβ1 is likely the main isoform expressed in liver, its role in human hepatocytes is not fully understood. Methods: To elucidate the role of THRβ1 action in human hepatocytes we used CRISPR/Cas9 editing to knock out THRβ1 in induced pluripotent stem cells (iPSC). Following directed differentiation to the hepatic lineage, iPSC-derived hepatocytes were then interrogated to determine the role of THRβ1 in ligand-independent and -dependent functions. Results: We found that the loss of THRβ1 promoted alterations in proliferation rate and metabolic pathways regulated by T3, including gluconeogenesis, lipid oxidation, fatty acid synthesis, and fatty acid uptake. We observed that key genes involved in liver metabolism are regulated through both T3 ligand-dependent and -independent THRβ1 signaling mechanisms. Finally, we demonstrate that following THRβ1 knockout, several key metabolic genes remain T3 responsive suggesting they are THRα targets. Conclusions: These results highlight that iPSC-derived hepatocytes are an effective platform to study mechanisms regulating TH signaling in human hepatocytes.http://www.sciencedirect.com/science/article/pii/S2212877824001881iPSC-derived hepatocytesTHRBThyroid hormoneLiver metabolism |
| spellingShingle | Lorraine Soares De Oliveira Joseph E. Kaserman Anne H. Van Der Spek Nora J. Lee Hendrik J. Undeutsch Rhiannon B. Werder Andrew A. Wilson Anthony N. Hollenberg Thyroid hormone receptor beta (THRβ1) is the major regulator of T3 action in human iPSC-derived hepatocytes Molecular Metabolism iPSC-derived hepatocytes THRB Thyroid hormone Liver metabolism |
| title | Thyroid hormone receptor beta (THRβ1) is the major regulator of T3 action in human iPSC-derived hepatocytes |
| title_full | Thyroid hormone receptor beta (THRβ1) is the major regulator of T3 action in human iPSC-derived hepatocytes |
| title_fullStr | Thyroid hormone receptor beta (THRβ1) is the major regulator of T3 action in human iPSC-derived hepatocytes |
| title_full_unstemmed | Thyroid hormone receptor beta (THRβ1) is the major regulator of T3 action in human iPSC-derived hepatocytes |
| title_short | Thyroid hormone receptor beta (THRβ1) is the major regulator of T3 action in human iPSC-derived hepatocytes |
| title_sort | thyroid hormone receptor beta thrβ1 is the major regulator of t3 action in human ipsc derived hepatocytes |
| topic | iPSC-derived hepatocytes THRB Thyroid hormone Liver metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S2212877824001881 |
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