Non-alcoholic fatty liver disease (NAFLD) and impaired glycaemic control are closely linked, however, the pathophysiological mechanisms underpinning this bidirectional relationship remain unresolved. The high secretory capacity of the liver and impairments in protein secretion in NAFLD suggest that endocrine changes in the liver are likely to contribute to glycaemic defects. We identify hexosaminidase A (HEXA) as a NAFLD-induced hepatokine in both mice and humans. HEXA regulates sphingolipid metabolism, converting GM2 to GM3 gangliosides; sphingolipids that are primarily localized to cell surface lipid rafts. Using recombinant murine HEXA protein, an enzymatically inactive HEXA(R178H) mutant, or adeno-associated viral vectors to induce hepatocyte-specific overexpression of HEXA, we show that HEXA improves blood glucose control by increasing skeletal muscle glucose uptake in mouse models of insulin resistance and type 2 diabetes, with these effects being dependent on HEXA’s enzymatic action. Mechanistically, HEXA remodels muscle lipid raft ganglioside composition, thereby increasing insulin-like growth factor 1 signalling and glucose transporter 4 localization to the cell surface. Disrupting lipid rafts reverses these HEXA-mediated effects. Together, this study identifies a novel pathway for inter-tissue communication between liver and skeletal muscle in the regulation of systemic glycaemic control.

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