ATP10A has a protective and sex‐specific role in lipid metabolism

Abstract

Genetic predisposition and environment play substantial roles in obesity, type 2 diabetes and cardiovascular disease (CVD). Genetic association studies have linked ATP10A, encoding a type IV P‐type ATPase (P4‐ATPase), to human metabolic disease. ATP10A is a lipid flippase that catalyzes the membrane translocation of phosphatidylcholine and glucosylceramide. These lipids and their respective metabolites have been independently implicated in metabolic dysfunction. To explore the role of this flippase in metabolism, we created a novel Atp10aknockout (KO) mouse model. Atp10a KO mice display a female‐specific weight gain during high‐fat diet feeding and this is attributable to increased adiposity. Female Atp10a KO mice also exhibit elevated plasma free fatty acids, cholesterol, and triglycerides, as well as a depletion in eicosanoid species compared to the wild type (WT) littermates. Additionally, female Atp10a KO mice exhibit elevated fasting blood glucose levels without compensatory elevation of insulin. We also found that the liver of female Atp10aKO mice displays larger lipid droplets, which was associated with increased diacylglycerol acyltransferase‐2 (DGAT2) expression and an attenuation of the insulin signaling pathway compared to the WT littermates. Thus far, our studies have shown that knocking out Atp10a in mice on a high fat diet results in sex‐specific perturbations to body composition, plasma lipid levels, glucose homeostasis, and liver metabolism. We have recently found that ATP10A is specifically expressed in the endothelial cells of multiple tissues. We are now exploring these metabolic phenotypes through the lens of endothelial cell dysfunction. These studies suggest mechanisms by which this flippase contributes to the development of CVD with obesity.