Crosstalk between TM4SF5 and GLUT8 regulates fructose metabolism in hepatic steatosis

Objective: Transmembrane 4 L six family member 5 (TM4SF5) is likely involved in non-alcoholic steatohepatitis, although its roles and cross-talks with glucose/fructose transporters in phenotypes derived from high-carbohydrate diets remain unexplored. Here, we investigated the modulation of hepatic fructose metabolism by TM4SF5. Methods: Wild-type or Tm4sf5^−/− knockout mice were evaluated via different diets, including normal chow, high-sucrose diet, or high-fat diet without or with fructose in drinking water (30% w/v). Using liver tissues and blood samples from the mice or hepatocytes, the roles of TM4SF5 in fructose-mediated de novo lipogenesis (DNL) and steatosis via a crosstalk with glucose transporter 8 (GLUT8) were assessed. Results: Tm4sf5 suppression or knockout in both in vitro and in vivo models reduced fructose uptake, DNL, and steatosis. Extracellular fructose treatment of hepatocytes resulted in an inverse relationship between fructose–uptake activity and TM4SF5-mediated translocalization of GLUT8 through dynamic binding at the cell surface. Following fructose treatment, TM4SF5 binding to GLUT8 transiently decreased with translocation to the plasma membrane (PM), where GLUT8 separated and became active for fructose uptake and DNL. Conclusions: Overall, hepatic TM4SF5 modulated GLUT8 localization and activity through transient binding, leading to steatosis-related fructose uptake and lipogenesis. Thus, TM4SF5 and/or GLUT8 may be promising treatment targets against liver steatosis resulting from excessive fructose consumption.