Flipping the Narrative: ATP10A's Multifaceted Influence on Lipid Metabolism, Endothelial Function, and Fertility

Abstract

Metabolic syndrome, cardiovascular disease, and infertility are pressing global health concerns that necessitate an in-depth exploration of their genetic underpinnings. One such genetic determinant is ATP10A, a flippase that translocates phosphatidylcholine and glucosylceramide from the outer to the inner leaflet of the plasma membrane. To explore the role of ATP10A in metabolism, endothelial function, and fertility we employed murine and cellular models of Atp10A deficiency. Using our novel Atp10A knockout mouse model, we discovered that knockout mice fed a high fat diet displayed female-specific dyslipidemia, characterized by elevated plasma levels of triglycerides, free fatty acids, and cholesterol, alongside changes in sphingolipid, eicosanoid, and bile acid levels. Additionally, female Atp10A knockout mice display hepatic insulin resistance without changes to whole-body glucose homeostasis. We also discovered that ATP10A is expressed in endothelial cells in liver and visceral fat. Further, investigations using endothelial cell culture models revealed that Atp10A deficiency results in endothelial dysfunction marked by perturbed insulin-dependent signaling. We also found high levels of ATP10A expressed in testes and vas deferens and the Atp10A knockout male mice exhibit smaller testes, oligozoospermia, asthenozoospermia, elevated circulating testosterone levels, and histopathological abnormalities as well as changes to gonadotropin dependent signaling in the testes. Altogether, these findings unveil ATP10A as an important genetic factor influencing metabolism, endothelial cell homeostasis, and fertility; offering valuable insights for future research and potential therapeutic interventions.