ATP10A promotes endothelial cell insulin sensitivity and protects against diet-induced dyslipidemia in female mice.

Endothelial dysfunction is strongly associated with metabolic and cardiovascular disease but how genetic and environmental factors intersect to promote disease progression remains elusive. Genetic association studies have linked ATP10A and closely related type IV P-type ATPases (P4-ATPases) to insulin resistance and vascular complications, such as atherosclerosis. Here, we generated Atp10A knockout mice and show that Atp10A deficiency results in female-specific dyslipidemia, independent of diet-induced obesity, characterized by elevated plasma triglycerides, free fatty acids and cholesterol, as well as altered VLDL and HDL properties. We also observed increased circulating levels of several sphingolipid species and reduced eicosanoids and bile acids levels. Additionally, the Atp10A-/- mice display hepatic insulin resistance without perturbations to whole-body glucose homeostasis. ATP10A is expressed in vascular and lymphatic endothelial cells, where reduced expression causes hyperactive insulin signaling at basal insulin levels and an inability to properly respond to added insulin. This unique form of insulin resistance suggests that ATP10A promotes insulin receptor desensitization to maintain endothelial cell insulin sensitivity. These findings may lead to therapeutic approaches to enhance ATP10A expression and improve vascular health and lipid metabolic profiles.