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

• Published in: Nature communications 2023-05, Vol.14 (1), p.2748-2748, Article 2748
• Main Authors: Druzak, Samuel A., Tardelli, Matteo, Mays, Suzanne G., El Bejjani, Mireille, Mo, Xulie, Maner-Smith, Kristal M., Bowen, Thomas, Cato, Michael L., Tillman, Matthew C., Sugiyama, Akiko, Xie, Yang, Fu, Haian, Cohen, David E., Ortlund, Eric A.
• Format: Article
• Language: English
• Subjects: 13; 13/106; 14; 38; 38/61; 38/77; 38/91; 42/47; 42/89; 45; 45/61; 45/70; 49; 59; 631/45/612/388; 64; 64/110; 692/699/1503/1607; 692/699/317; 82/83; Adipose tissue; Animals; Cell membranes; Choline; Complementation; Data points; Deletion; Diet; Fatty liver; Fatty Liver - genetics; Fatty Liver - metabolism; Fatty Liver - prevention & control; Gene expression; Hepatocytes; High fat diet; Humanities and Social Sciences; Lecithin; Ligands; Lipid transfer proteins; Lipid-binding protein; Lipids; Liver; Liver - metabolism; Male; Males; Metabolism; Methionine; Mice; Mouse devices; multidisciplinary; Peroxisome proliferator-activated receptors; Phenotypes; Phosphatidylcholine; Phosphatidylcholine transfer protein; Phosphatidylcholines - metabolism; Phospholipids; PPAR delta - genetics; Protein transport; Proteins; Science; Science & Technology - Other Topics; Science (multidisciplinary); Skeletal muscle; Starvation; Steatosis; Triglycerides
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-38010-w

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. Deletion of PC-TP has many beneficial effects, mostly ascribed to its role in regulating THEM2. Here, the authors show a novel interaction between PC-TP and PPARδ that explains aspects of the beneficial metabolic phenotype associated with PC-TP deletion.