At the level of systems physiology, hepatocyte GLUT8 deletion is sufficient to enhance peripheral caloric expenditure, attenuate high-fructose diet–induced peripheral fat accumulation, and ameliorate hepatocellular damage, steatosis, and inflammatory marker gene expression in multiple models of progressive metabolic dysfunction–associated steatotic liver disease (MASLD) and MASH. Here, SLC2A8 is linked to metabolic dysfunction-associated steatohepatitis.