Abstract
Trehalose is a disaccharide demonstrated to mitigate disease burden in multiple murine neurodegenerative models. We recently revealed that trehalose rapidly induces hepatic autophagy and abrogates hepatic steatosis by inhibiting hexose transport via the SLC2A family of facilitative transporters. Prior studies, however, postulate that intracellular trehalose is sufficient to induce cellular autophagy. The objective of the current study was to identify the means by which trehalose accesses the hepatocyte cytoplasm, and define the distal signaling mechanisms by which trehalose induces autophagy. We provide gas chromatographic/mass spectrometric, fluorescence microscopic and radiolabeled uptake evidence that trehalose traverses the plasma membrane via SLC2A8 (GLUT8), a homolog of the trehalose transporter-1 (Tret1). Moreover, GLUT8-deficient hepatocytes and GLUT8-deficient mice exposed to trehalose resisted trehalose-induced AMP-activated protein kinase (AMPK) phosphorylation and autophagic induction in vitro and in vivo. Although trehalose profoundly attenuated mTORC1 signaling, trehalose-induced mTORC1 suppression was insufficient to activate autophagy in the absence of AMPK or GLUT8. Strikingly, transient, heterologous Tret1 overexpression reconstituted autophagic flux and AMPK signaling defects in GLUT8-deficient hepatocyte cultures. Together, these data suggest that cytoplasmic trehalose access is carrier-mediated, and that GLUT8 is a mammalian trehalose transporter required for hepatocyte trehalose-induced autophagy and signal transduction.
Highlights
Trehalose is a disaccharide demonstrated to mitigate disease burden in multiple murine neurodegenerative models
We further provide evidence that GLUT8 is essential for trehalose-induced activation of the AMPK-ULK1 pathway and autophagic flux in a way that is genetically complemented by heterologous Tret[1] expression
We tested whether the primary amino acid sequences of human GLUT8 and its closely related class III GLUT homologs significantly aligned with specialized trehalose transporter proteins, drosophila Tret[1] and Tret[1,2], using ClustalΩ (Fig. 1A)
Summary
Trehalose is a disaccharide demonstrated to mitigate disease burden in multiple murine neurodegenerative models. Transient, heterologous Tret[1] overexpression reconstituted autophagic flux and AMPK signaling defects in GLUT8-deficient hepatocyte cultures. Together, these data suggest that cytoplasmic trehalose access is carrier-mediated, and that GLUT8 is a mammalian trehalose transporter required for hepatocyte trehalose-induced autophagy and signal transduction. Trehalose is a disaccharide previously demonstrated to induce autophagy and mitigate multiple disease models through incompletely defined mechanisms[3,4,5,6,7,8,9]. The glucose transporter (GLUT, encoded by slc2a genes) family of transmembrane-spanning facilitative carbohydrate transporters are ubiquitously expressed carriers that mediate transport of carbohydrates and other substrates down their concentration gradients across lipid bilayers[11]. Despite identification of facilitative trehalose transport in lower organisms[20], the means by which a disaccharide could efficiently access the interior of a mammalian cell is heretofore unknown
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