Solute carrier 5A5 regulates systemic glucose homeostasis by mediating glucose absorption in the Drosophila midgut

Abstract

The small intestine is the first organ that is exposed to and absorbs dietary glucose and thus represents the first of a continuum of events that modulates normal systemic glucose homeostasis. A better understanding of the regulation of intestinal glucose transporters is therefore pertinent to our efforts in curbing metabolic disorders. However, so far, the mechanisms known to regulate SGLT1, the primary intestinal glucose transporter, are mainly elucidated from in vitro studies. The Drosophila midgut, functional equivalence of the small intestine, could serve as an efficient in vivo model system for studying intestinal glucose transporter regulation; however, no glucose transporter has yet been identified in the midgut. Here, we report that the Drosophila Solute Carrier 5A5 (dSLC5A5) is homologous to SGLT1 and is highly expressed in the midgut. The knockdown of dSLC5A5 decreases systemic and circulating sugar levels and decreases glucose uptake into the enterocytes. In contrary, the overexpression of dSLC5A5 elevates systemic and circulating sugar levels and promotes glucose uptake into the enterocytes. We show that dSLC5A5 undergoes dynamin-dependent endocytosis in the enterocyte apical membrane, and that dSLC5A5 endocytosis is essential for the glucose uptake capability of dSLC5A5. Moreover, we provide evidence supporting that intracellular lysosomal degradation of endocytosed dSLC5A5 plays a significant role in the maintenance of dSLC5A5 level in the enterocyte apical membrane. We further show that short-term exposure to glucose upregulates SLC5A5 abundance in the enterocyte apical membrane. Finally, we show that the loss or gain of dSLC5A5 ameliorates or exacerbates the high sugar diet (HSD)-mediated glucose metabolic defects. Together, our studies uncovered the first Drosophila glucose transporter in the midgut and reveal new mechanisms that regulate glucose transporters in the enterocyte apical membranes.