Glycogen Architecture Dysregulation in Metabolic Dysfunction-Associated Steatohepatitis (MASH): A Therapeutic Avenue via Glycogen Homeostasis

Abstract Metabolic dysfunction-associated steatohepatitis (MASH) is the inflammatory phase of the metabolic dysfunction-associated steatotic liver disease (MASLD) spectrum, and can progress to fibrosis and even carcinoma; currently, there are few effective therapies. The complex branched glucose polymer glycogen is found in significant quantities in the liver; it comprises “β particles”, ~20 nm in size, bound as aggregate “α particles”, up to hundreds of nm in size. The role of liver glycogen in MASLD and MASH is unknown. Size-exclusion chromatography, fluorophore-assisted carbohydrate electrophoresis and transmission electron microscopy show that, compared with healthy controls, MASLD livers exhibited a higher β-particle content (32.6% vs 40.7%, P <0.05) and a 5 % longer average chain length (ACL); MASH amplified these defects: β-particle fraction rose to 46.1% (P <0.001 vs. control) and ACL to 26 % (P <0.0001 vs. control), indicating this is an early, shared disruption in different stages of MASLD. The glycogen-related proteins (AGL, GBE, GYS, PYGL and PPP1R3B) exhibit opposite trajectories in MASLD and MASH. Therapeutic dietary polyphenols, despite disparate effects on individual glycogen-related enzymes, all reversed aberrant glycogen architecture by increasing α-particle proportions and decreasing chain lengths. Our findings offer a mechanistic blueprint whereby glycogen structure characterization might guide clinical therapeutic strategy.