Ligand dependent interaction between PC-TP and PPARδ mitigates diet-induced hepatic steatosis in male mice

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 and Eric A. Ortlund ()
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Samuel A. Druzak: Emory University School of Medicine
Matteo Tardelli: Weill Cornell Medical College
Suzanne G. Mays: Emory University School of Medicine
Mireille El Bejjani: Emory University School of Medicine
Xulie Mo: Emory University School of Medicine
Kristal M. Maner-Smith: Emory University School of Medicine
Thomas Bowen: Emory University School of Medicine
Michael L. Cato: Emory University School of Medicine
Matthew C. Tillman: Emory University School of Medicine
Akiko Sugiyama: Weill Cornell Medical College
Yang Xie: Weill Cornell Medical College
Haian Fu: Emory University School of Medicine
David E. Cohen: Weill Cornell Medical College
Eric A. Ortlund: Emory University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38010-w

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