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

• Type of Material: Article
• Authors: Samuel A. Druzak, Emory University; Matteo Tardelli, Weill Cornell Medicine; Suzanne G. Mays, Emory University; Mireille El Bejjani, Emory University; Xulie Mo, Emory University; Kristal M. Maner-Smith, Emory University; Thomas Bowen, Emory University; Michael L. Cato, Emory University; Matthew C. Tillman, Emory University; Akiko Sugiyama, Weill Cornell Medicine; Yang Xie, Weill Cornell Medicine; Haian Fu, Emory University; David E. Cohen, Weill Cornell Medicine; Eric Ortlund, Emory University
• Language: English
• Date: 2023-12-01
• Publisher: Nature
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-023-38010-w
• Title of Journal or Parent Work: Nature Communications
• Volume: 14
• Issue: 1
• Start Page: 2748
• End Page: 2748
• Grant/Funding Information: A F31 training fellowship from the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK), F31 DK 126435 and training grant T32 GM 008602 supported S.A.D during the duration of this work. This work was supported by the NIH (R01 DK 048873, DK 056626 and DK 103046 to D.E.C. and E.A.O.). M.L.C. was supported by T32 GM 008367-29 This study was supported in part by the Emory Integrated Metabolomics and Lipidomics Core, which is subsidized by the Emory University School of Medicine, and is one of the Emory Integrated Core Facilities. Additional support was provided by the Georgia Clinical and Translational Science Alliance of the NIH, Award UL1 TR 002378. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the NIH.
• Keywords: Mice; Diet; PPAR delta; Ligands; Liver; Animals; Male; Fatty Liver; Phosphatidylcholines
• Research Categories: Health Sciences, Nutrition; Biology, Cell

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.