Hepatic Neu1 deficiency drives metabolic dysregulation via GCGR desialylation-dependent cAMP-PKA signaling and...

Neuraminidase 1 (Neu1) plays a crucial role in the removal of sialic acid from glycoproteins and glycolipids, significantly influencing hepatic glycolipid metabolism. However, its precise contributions to liver gluconeogenesis and bile acid metabolism are not well defined. Although the sialylation of the hepatic glucagon receptor (GCGR) has been linked to the regulation of hepatic glucose homeostasis, the impact of Neu1 on hepatic gluconeogenesis through the desialylation of GCGR remains to be elucidated.

To explore the physiological function of Neu1 in liver glycolipid metabolism, we constructed liver-specific Neu1 knockout mice. Glucagon induced HepG2 cells were used to assess the role of Neu1 in gluconeogenesis.

Phenotypic analysis indicated that these knockout mice exhibited a late-onset glycolipid metabolism disorder. Mechanistically, Neu1 deficiency caused the upregulation of key gluconeogenic genes, with cAMP-PKA signaling and the sialylation mediated activation of GCGR influencing the Akt-FoxO1 pathway, contributing to the disruption of hepatic glucose metabolism in 21-month-old Neu1 deficient mice. Transcriptomic analysis revealed an increase in lipogenesis and bile acid synthesis pathways in the livers of aged Neu1 knockout mice. Notably, there were significant alterations in steroid hormone biosynthesis, with elevated levels of lithocholic acid and allolithocholic acid detected in the Neu1 deficient mice. Additionally, the activation of inflammatory responses and reduced lipolysis seemed to correlate with the observed abnormalities in glycolipid metabolism.

These results indicate that Neu1 is essential for GCGR-dependent gluconeogenesis, suggesting that Neu1 could be a potential therapeutic target for addressing hepatic glycolipid metabolism disorders associated with aging.