Liver-secreted hexosaminidase a regulates insulin-like growth factor signaling and glucose transport in skeletal muscle

Abstract

Nonalcoholic fatty liver disease (NAFLD) and impaired glycemic 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 glycemic defects. We identify hexosaminidase A (HEXA) as an 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 recombinantmurineHEXA protein, an enzymatically inactiveHEXA(R178H)mutant, or a..