Figure 7.

Overview showing function of SLC37A4 in hepatocytes

A schematic showing the function of wild-type SLC37A4 in hepatocytes during nourished or fasting conditions. Under nourished conditions, exogenous Glc provides ample Glc-6P for glycolysis, glycogenesis, and pentose phosphate pathways. Under fasting conditions, hepatocytes must generate Glc-6P from glycogenolysis (GL) and gluconeogenesis (GNG) for these pathways and also normalize plasma Glc. SLC37A4 imports Glc-6P into the ER and G6PC releases Pi+Glc so both can be returned to the cytoplasm and Glc to the circulation. Mutant SLC37A4 (p.Arg423^∗) is fully active and maintains normal glucose homeostasis under fasting conditions, but a portion of the active transporter becomes mislocalized to an undefined, spatially restricted pre-Golgi/post-ER compartment, possibly ERES. Glc-6P and/or Pi accumulates there, leading to a dose-dependent reduction of Golgi pH and Golgi architecture/homeostasis. Reduced pH is propagated in subsequent Golgi compartments, altering the activity and/or localization of multiple N- and O-glycan-modifying enzymes. Because Mn and Mg are critical co-factors for many of these reactions, reduced pH could affect their solubility and availability.