Ligand dependent interaction between PC-TP and PPARδ mitigates diet-induced hepatic steatosis in male mice.
Samuel A DruzakMatteo TardelliSuzanne G MaysMireille El BejjaniXulie MoKristal M Maner-SmithThomas BowenMichael L CatoMatthew C TillmanAkiko SugiyamaYang XieHaian FuDavid E CohenEric A OrtlundPublished in: Nature communications (2023)
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.
Keyphrases
- insulin resistance
- adipose tissue
- high fat diet
- fatty acid
- skeletal muscle
- binding protein
- signaling pathway
- physical activity
- metabolic syndrome
- body mass index
- endothelial cells
- stem cells
- gene expression
- high fat diet induced
- weight loss
- wild type
- single cell
- radiation therapy
- radiation induced
- heat stress
- heat shock
- protein protein
- genome wide