Targeting hepatocyte-specific SLC2A8 blocks hepatic steatosis and dissociates TCA cycle flux inhibition from glutamine anaplerosis.

ABSTRACT:

Background

Excess TCA cycle and glutamine anaplerosis are hallmarks of metabolic dysfunction-associated steatotic liver disease and steatohepatitis. Blocking glutamine metabolism attenuates metabolic dysfunction-associated steatohepatitis. However, inhibiting TCA cycle flux by blocking plasma membrane carbohydrate transport is limited by the ubiquitous tissue distribution, function, and homology among the SLC2A family of facilitative carbohydrate transporters, and the potential for carbohydrate blockade to invoke or exacerbate glutamine anaplerosis. Here, we quantify alterations in hepatocyte carbon flux, define the broader metabolic consequences of hepatocyte-specific GLUT8/SLC2A8 inhibition, and delineate the antisteatotic efficacy of a novel small-molecule GLUT8-selective inhibi

SUBMITTER: Adams JA 

PROVIDER: S-EPMC12456581 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature