ZIP13 regulates lipid metabolism by changing intracellular iron and zinc balance

Abstract

AbstractMetabolic diseases are caused by a prolonged energy imbalance, and adipose tissue is known to be the main contributor. We previously reported that ZIP13, an Slc39a transporter whose deficiency causes Ehlers-Danlos syndrome spondylocheirodysplastic type 3 associated with lipoatrophy, inhibits the adipocyte browning pathway by modulating intracellular zinc status. The precise mechanisms of how ZIP13 regulates the homeostasis of adipose tissue remain unclear and therefore, we investigated the role of ZIP13 in mature adipocytes using adipocyte-specificZip13-deficient mice. We herein demonstrate that these mice show accelerated lipolysis and reduced respiratory exchange ratio. In addition, abundance of iron and zinc balance were altered during differentiation in normal adipocytes, whereas iron distribution was substantially affected inZip13-deficient adipocytes, which downregulated PDE activity and enhanced β-adrenergic receptor signaling pathways. Importantly, we confirmed that ZIP13 could transport both zinc and iron, using theXenopusoocyte transport system andin silicostructural dynamics simulations, and that the defect in iron distribution perturbs proper lipolysis. Together, these results illustrate that ZIP13 acts as a key regulator for lipolysis in adipocytes via the proper use of metals, and that the ZIP13-iron axis plays an important role in regulation of lipid metabolism.