Ligand dependent interaction between PC-TP and PPARδ mitigates diet-induced hepatic steatosis in male mice
Abstract Phosphatidylcholine transfer protein (PC-TP; synonym StarD2) is a soluble lipid-binding protein that transports phosphatidylcholine (PC) between cellular membranes. To better understand the protective metabolic effects associated with hepatic PC-TP, we generated a hepatocyte-specific PC-TP...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
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Nature Portfolio
2023-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38010-w |
| _version_ | 1827948088804769792 |
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| author | Samuel A. Druzak Matteo Tardelli Suzanne G. Mays Mireille El Bejjani Xulie Mo Kristal M. Maner-Smith Thomas Bowen Michael L. Cato Matthew C. Tillman Akiko Sugiyama Yang Xie Haian Fu David E. Cohen Eric A. Ortlund |
| author_facet | Samuel A. Druzak Matteo Tardelli Suzanne G. Mays Mireille El Bejjani Xulie Mo Kristal M. Maner-Smith Thomas Bowen Michael L. Cato Matthew C. Tillman Akiko Sugiyama Yang Xie Haian Fu David E. Cohen Eric A. Ortlund |
| author_sort | Samuel A. Druzak |
| collection | DOAJ |
| description | Abstract Phosphatidylcholine transfer protein (PC-TP; synonym StarD2) is a soluble lipid-binding protein that transports phosphatidylcholine (PC) between cellular membranes. To better understand the protective metabolic effects associated with hepatic PC-TP, we generated a hepatocyte-specific PC-TP knockdown (L-Pctp −/−) in male mice, which gains less weight and accumulates less liver fat compared to wild-type mice when challenged with a high-fat diet. Hepatic deletion of PC-TP also reduced adipose tissue mass and decreases levels of triglycerides and phospholipids in skeletal muscle, liver and plasma. Gene expression analysis suggest that the observed metabolic changes are related to transcriptional activity of peroxisome proliferative activating receptor (PPAR) family members. An in-cell protein complementation screen between lipid transfer proteins and PPARs uncovered a direct interaction between PC-TP and PPARδ that was not observed for other PPARs. We confirmed the PC-TP– PPARδ interaction in Huh7 hepatocytes, where it was found to repress PPARδ-mediated transactivation. Mutations of PC-TP residues implicated in PC binding and transfer reduce the PC-TP-PPARδ interaction and relieve PC-TP-mediated PPARδ repression. Reduction of exogenously supplied methionine and choline reduces the interaction while serum starvation enhances the interaction in cultured hepatocytes. Together our data points to a ligand sensitive PC-TP– PPARδ interaction that suppresses PPAR activity. |
| first_indexed | 2024-04-09T12:48:53Z |
| format | Article |
| id | doaj.art-dffadf07d2f544bda1ee583c85133fb6 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-09T12:48:53Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-dffadf07d2f544bda1ee583c85133fb62023-05-14T11:21:59ZengNature PortfolioNature Communications2041-17232023-05-0114111610.1038/s41467-023-38010-wLigand dependent interaction between PC-TP and PPARδ mitigates diet-induced hepatic steatosis in male miceSamuel A. Druzak0Matteo Tardelli1Suzanne G. Mays2Mireille El Bejjani3Xulie Mo4Kristal M. Maner-Smith5Thomas Bowen6Michael L. Cato7Matthew C. Tillman8Akiko Sugiyama9Yang Xie10Haian Fu11David E. Cohen12Eric A. Ortlund13Department of Biochemistry, Emory University School of MedicineJoan & Sanford I. Weill Department of Medicine, Weill Cornell Medical CollegeDepartment of Biochemistry, Emory University School of MedicineDepartment of Biochemistry, Emory University School of MedicineDepartment of Chemical Biology and Pharmacology, Emory University School of MedicineEmory Integrated Lipidomics and Metabolomics Core, Emory University School of MedicineEmory Integrated Lipidomics and Metabolomics Core, Emory University School of MedicineDepartment of Biochemistry, Emory University School of MedicineDepartment of Biochemistry, Emory University School of MedicineJoan & Sanford I. Weill Department of Medicine, Weill Cornell Medical CollegeJoan & Sanford I. Weill Department of Medicine, Weill Cornell Medical CollegeDepartment of Chemical Biology and Pharmacology, Emory University School of MedicineJoan & Sanford I. Weill Department of Medicine, Weill Cornell Medical CollegeDepartment of Biochemistry, Emory University School of MedicineAbstract Phosphatidylcholine transfer protein (PC-TP; synonym StarD2) is a soluble lipid-binding protein that transports phosphatidylcholine (PC) between cellular membranes. To better understand the protective metabolic effects associated with hepatic PC-TP, we generated a hepatocyte-specific PC-TP knockdown (L-Pctp −/−) in male mice, which gains less weight and accumulates less liver fat compared to wild-type mice when challenged with a high-fat diet. Hepatic deletion of PC-TP also reduced adipose tissue mass and decreases levels of triglycerides and phospholipids in skeletal muscle, liver and plasma. Gene expression analysis suggest that the observed metabolic changes are related to transcriptional activity of peroxisome proliferative activating receptor (PPAR) family members. An in-cell protein complementation screen between lipid transfer proteins and PPARs uncovered a direct interaction between PC-TP and PPARδ that was not observed for other PPARs. We confirmed the PC-TP– PPARδ interaction in Huh7 hepatocytes, where it was found to repress PPARδ-mediated transactivation. Mutations of PC-TP residues implicated in PC binding and transfer reduce the PC-TP-PPARδ interaction and relieve PC-TP-mediated PPARδ repression. Reduction of exogenously supplied methionine and choline reduces the interaction while serum starvation enhances the interaction in cultured hepatocytes. Together our data points to a ligand sensitive PC-TP– PPARδ interaction that suppresses PPAR activity.https://doi.org/10.1038/s41467-023-38010-w |
| spellingShingle | Samuel A. Druzak Matteo Tardelli Suzanne G. Mays Mireille El Bejjani Xulie Mo Kristal M. Maner-Smith Thomas Bowen Michael L. Cato Matthew C. Tillman Akiko Sugiyama Yang Xie Haian Fu David E. Cohen Eric A. Ortlund Ligand dependent interaction between PC-TP and PPARδ mitigates diet-induced hepatic steatosis in male mice Nature Communications |
| title | Ligand dependent interaction between PC-TP and PPARδ mitigates diet-induced hepatic steatosis in male mice |
| title_full | Ligand dependent interaction between PC-TP and PPARδ mitigates diet-induced hepatic steatosis in male mice |
| title_fullStr | Ligand dependent interaction between PC-TP and PPARδ mitigates diet-induced hepatic steatosis in male mice |
| title_full_unstemmed | Ligand dependent interaction between PC-TP and PPARδ mitigates diet-induced hepatic steatosis in male mice |
| title_short | Ligand dependent interaction between PC-TP and PPARδ mitigates diet-induced hepatic steatosis in male mice |
| title_sort | ligand dependent interaction between pc tp and pparδ mitigates diet induced hepatic steatosis in male mice |
| url | https://doi.org/10.1038/s41467-023-38010-w |
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