Abstract

Dysregulated hepatic gluconeogenesis driven by glucagon is a key contributor to hyperglycemia in diabetes, yet the molecular mechanisms that restrain this pathway remain incompletely understood. This study reveals neuraminidase 1 (NEU1) as a suppressor of hepatic glucagon-driven gluconeogenesis in diabetes. We found that glucagon challenge downregulates hepatic NEU1 expression, inversely correlating with fasting blood glucose levels in individuals with diabetes. Functionally, liver-specific NEU1 overexpression antagonizes hepatic gluconeogenesis in glucagon-challenged mice and high fat diet (HFD)-fed mice, while NEU1 knockout augments glucagon response. Additionally, NEU1 inhibits hepatic gluconeogenesis in a non-enzymatic manner. Mechanistically, NEU1 interacts with SAM68 to activate GCN5 promoter, leading to increase of PGC-1α acetylation. The inhibitory effect of NEU1 overexpression on gluconeogenesis is abrogated by GCN5 knockdown in HFD-fed mice. A NEU1-targeted screening strategy identified α-hederin and oleanolic acid as synergistic inhibitors of hepatic glucagon response through NEU1 stabilization and SAM68 binding enhancement. Here we show an inhibitory role of NEU1 in the hepatic glucagon response and suggest a potential avenue for targeting NEU1 to treat diabetes.