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PMON184 Ligand-dependent interaction between phosphatidylcholine transfer protein and PPARδ: therapeutic implications for metabolic syndrome

Phosphatidylcholine transfer protein (PC-TP; synonym StarD2) is a soluble lipid binding protein that transports phosphatidylcholine (PC) between cellular membranes. PC-TP knockout mice are more sensitive to glucose and insulin, have increased beta oxidation and improved liver health compared to wild...

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Autores principales: Druzak, Samuel, Tardelli, Matteo, Mays, Suzanne, Bejjani, Mireille, Cato, Micheal, Tillman, Matthew, Cohen, David, Mo, Xiulei, Fu, Haian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9627842/
http://dx.doi.org/10.1210/jendso/bvac150.1222
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author Druzak, Samuel
Tardelli, Matteo
Mays, Suzanne
Bejjani, Mireille
Cato, Micheal
Tillman, Matthew
Cohen, David
Mo, Xiulei
Fu, Haian
author_facet Druzak, Samuel
Tardelli, Matteo
Mays, Suzanne
Bejjani, Mireille
Cato, Micheal
Tillman, Matthew
Cohen, David
Mo, Xiulei
Fu, Haian
author_sort Druzak, Samuel
collection PubMed
description Phosphatidylcholine transfer protein (PC-TP; synonym StarD2) is a soluble lipid binding protein that transports phosphatidylcholine (PC) between cellular membranes. PC-TP knockout mice are more sensitive to glucose and insulin, have increased beta oxidation and improved liver health compared to wild-type mice. To better understand the protective metabolic effects associated with PC-TP deletion, we investigated how hepatic PC-TP affects lipid metabolism, sensitivity to glucose and insulin, and energy homeostasis in a mouse model of diet-induced obesity. We generated a liver-specific PC-TP knockout mouse (L-Pctp-/-), 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 reduces levels of triglycerides and phospholipids in skeletal muscle, suggesting that PC-TP in the liver influences lipid metabolism in the muscle. Gene expression analyses 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 novel, direct interaction between PC-TP and PPARδ that was not observed for other PPAR family members. 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 combined with a reduction of exogenously supplied lipids through serum starvation relieves PC-TP mediated PPAR repression. Together our data points to a ligand sensitive PC-TP– PPARδ interaction that suppresses PPAR activity. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
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spelling pubmed-96278422022-11-04 PMON184 Ligand-dependent interaction between phosphatidylcholine transfer protein and PPARδ: therapeutic implications for metabolic syndrome Druzak, Samuel Tardelli, Matteo Mays, Suzanne Bejjani, Mireille Cato, Micheal Tillman, Matthew Cohen, David Mo, Xiulei Fu, Haian J Endocr Soc Non-Steroid Hormone Signaling Phosphatidylcholine transfer protein (PC-TP; synonym StarD2) is a soluble lipid binding protein that transports phosphatidylcholine (PC) between cellular membranes. PC-TP knockout mice are more sensitive to glucose and insulin, have increased beta oxidation and improved liver health compared to wild-type mice. To better understand the protective metabolic effects associated with PC-TP deletion, we investigated how hepatic PC-TP affects lipid metabolism, sensitivity to glucose and insulin, and energy homeostasis in a mouse model of diet-induced obesity. We generated a liver-specific PC-TP knockout mouse (L-Pctp-/-), 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 reduces levels of triglycerides and phospholipids in skeletal muscle, suggesting that PC-TP in the liver influences lipid metabolism in the muscle. Gene expression analyses 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 novel, direct interaction between PC-TP and PPARδ that was not observed for other PPAR family members. 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 combined with a reduction of exogenously supplied lipids through serum starvation relieves PC-TP mediated PPAR repression. Together our data points to a ligand sensitive PC-TP– PPARδ interaction that suppresses PPAR activity. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m. Oxford University Press 2022-11-01 /pmc/articles/PMC9627842/ http://dx.doi.org/10.1210/jendso/bvac150.1222 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Non-Steroid Hormone Signaling
Druzak, Samuel
Tardelli, Matteo
Mays, Suzanne
Bejjani, Mireille
Cato, Micheal
Tillman, Matthew
Cohen, David
Mo, Xiulei
Fu, Haian
PMON184 Ligand-dependent interaction between phosphatidylcholine transfer protein and PPARδ: therapeutic implications for metabolic syndrome
title PMON184 Ligand-dependent interaction between phosphatidylcholine transfer protein and PPARδ: therapeutic implications for metabolic syndrome
title_full PMON184 Ligand-dependent interaction between phosphatidylcholine transfer protein and PPARδ: therapeutic implications for metabolic syndrome
title_fullStr PMON184 Ligand-dependent interaction between phosphatidylcholine transfer protein and PPARδ: therapeutic implications for metabolic syndrome
title_full_unstemmed PMON184 Ligand-dependent interaction between phosphatidylcholine transfer protein and PPARδ: therapeutic implications for metabolic syndrome
title_short PMON184 Ligand-dependent interaction between phosphatidylcholine transfer protein and PPARδ: therapeutic implications for metabolic syndrome
title_sort pmon184 ligand-dependent interaction between phosphatidylcholine transfer protein and pparδ: therapeutic implications for metabolic syndrome
topic Non-Steroid Hormone Signaling
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9627842/
http://dx.doi.org/10.1210/jendso/bvac150.1222
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