Abstract
Caenorhabditis elegans (C. elegans) is an attractive animal model for biological and biomedical research because it permits relatively easy genetic dissection of cellular pathways, including insulin/IGF-like signaling (IIS), that are conserved in mammalian cells. To explore C. elegans as a model system to study the regulation of the facilitative glucose transporter (GLUT), we have characterized the GLUT gene homologues in C. elegans: fgt-1, R09B5.11, C35A11.4, F53H8.3, F48E3.2, F13B12.2, Y61A9LA.1, K08F9.1 and Y37A1A.3. The exogenous expression of these gene products in Xenopus oocytes showed transport activity to unmetabolized glucose analogue 2-deoxy-D-glucose only in FGT-1. The FGT-1-mediated transport activity was inhibited by the specific GLUT inhibitor phloretin and exhibited a Michaelis constant (K m) of 2.8 mM. Mannose, galactose, and fructose were able to inhibit FGT-1-mediated 2-deoxy-D-glucose uptake (P < 0.01), indicating that FGT-1 is also able to transport these hexose sugars. A GFP fusion protein of FGT-1 was observed only on the basolateral membrane of digestive tract epithelia in C. elegans, but not in other tissues. FGT-1::eGFP expression was observed from early embryonic stages. The knockdown or mutation of fgt-1 resulted in increased fat staining in both wild-type and daf-2 (mammalian insulin receptor homologue) mutant animals. Other common phenotypes of IIS mutant animals, including dauer formation and brood size reduction, were not affected by fgt-1 knockdown in wild-type or daf-2 mutants. Our results indicated that in C. elegans, FGT-1 is mainly a mammalian GLUT2-like intestinal glucose transporter and is involved in lipid metabolism.
Highlights
Glucose is an essential energy source and substrate for the synthesis of macromolecules in most, if not all, living organisms
The BLASTP E-values of FGT-1 and R09B5.11 against hGLUT1 or hGLUT4 were 7E-82, 1E-66, 3E-84 and 6E-67, respectively, which were much lower than other candidates (> 2E-36 and > 5E-31 to hGLUT1 and hGLUT4, respectively) (Table S1)
BLASTP searches of the C. elegans genome with human GLUTs (hGLUTs) cDNAs and structural analyses resulted in nine C. elegans glucose transporter (GLUT) candidate genes: fgt-1, R09B5.11, C35A11.4, F53H8.3, F48E3.2, F13B12.2, Y61A9LA.1, K08F9.1, and Y37A1A.3
Summary
Glucose is an essential energy source and substrate for the synthesis of macromolecules in most, if not all, living organisms. The facilitated glucose transporters (GLUT, gene symbol: SLC2A) mediate passive glucose diffusion across the plasma membrane in most tissues, whereas Na+/ glucose cotransporters (SGLT, gene symbol: SLC5A) mediate Na+-dependent secondary active glucose transport mainly in the epithelial cells of the small intestine and kidney convoluted tubules [1,2]. GLUT4 mediates insulinregulated glucose uptake in muscle cells and adipocytes In these cells, insulin stimulates the translocation of GLUT4 from the intracellular pool to the plasma membrane and increases glucose uptake and utilization [9,10]. Insulin stimulates the translocation of GLUT4 from the intracellular pool to the plasma membrane and increases glucose uptake and utilization [9,10] This regulation plays a critical role in maintaining whole-body glucose homeostasis. GLUTs belong to the major facilitator superfamily (MFS), which consists of members that are present ubiquitously in bacteria, archaea, cyanobacteria, fungi, protozoa, plants and animals
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