Lipidomic analysis of TRPC1 Ca2+ permeable channel-knock out mouse demonstrates a vital role in placental tissue sphingolipid and triacylglycerol homeostasis under maternal high-fat diet

Authors: Bukowski, Michael; SINGH, BRIJI - University Of Texas At San Antonio; Roemmich, James; Larson, Kate

Submitted to: Frontiers in Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/14/2022
Publication Date: 3/10/2022
Citation: Bukowski, M.R., Singh, B.B., Roemmich, J.N., Claycombe-Larson, K.J. 2022. Lipidomic analysis of TRPC1 Ca2+ permeable channel-knock out mouse demonstrates a vital role in placental tissue sphingolipid and triacylglycerol homeostasis under maternal high-fat diet. Frontiers in Endocrinology. 13. Article 854269. https://doi.org/10.3389/fendo.2022.854269.
DOI: https://doi.org/10.3389/fendo.2022.854269

Interpretive Summary: The health of the placenta is critical to fetal growth and development. Obesity caused by eating a high-fat diet impacts placental health, adding lipid molecules that decrease the ability of the placenta to transport nutrients to the fetus and have been associated with the development of preeclampsia, a pregnancy complication affecting between 2% and 6% of pregnancies. In this work we demonstrate in a mouse model system that limiting calcium transport within the placenta promotes the build-up of lipid molecules that have been associated with preeclampsia. This is an important step in determining causes of this serious pregnancy complication.

Technical Abstract: The transient receptor potential canonical channel 1 (TRPC1) is a ubiquitous Ca2+-permeable integral membrane protein present in most tissues, including adipose and placenta, and functionally regulates energetic homeostasis. We demonstrated that elimination of TRPC1 in a mouse model increased body adiposity and limited adipose accumulation under a high fat diet (HFD) even under conditions of exercise. Additionally, intracellular Ca2+ regulates membrane lipid content via the activation of the protein kinase C pathway, which may impact placental membrane lipid content and structure. Based upon this we investigated the effect of HFD and TRPC1 elimination on neutral lipids (triacylglycerol and cholesteryl ester), membrane lipids (phosphatidylcholine and phosphatidylethanolamine), and other multifunctional lipid species (unesterified cholesterol, sphingomyelins, ceramides). The concentration of unesterified cholesterol and sphingomyelin increased with gestational age (E12.5 to E 18.5.) indicating possible increases in plasma membrane fluidity. Diet-dependent increases ceramide concentration at E12.5 suggest a pro-inflammatory role for HFD in early gestation. TRPC1-dependent decreases in cholesterol ester concentration with concomitant increases in long-chain polyunsaturated fatty acid -containing triacylglycerols indicate a disruption of neutral lipid homeostasis that may be tied to Ca2+ regulation. These results align with changes in lipid content observed in studies of preeclamptic human placenta.