Gamma-glutamyl carboxylated Gas6 facilitates the prophylactic effect of vitamin K in inhibiting hyperlipidemia-associated inflammatory pathophysiology via arresting MCP-1/ICAM-1 me diate d monocyte-hepatocyte adhesion

Role of growth arrest-specific 6 (Gas6), member of vitamin K (VK)-dependent protein family in hyperlipidemia-associated inflammation remains unresolved. To address this, blood samples were collected from hyperlipidemic subjects and age-matched healthy controls and observed that gamma-glutamyl carboxylated Gas6 (Gla-Gas6) but not total Gas6 were significantly lower while pro-inflammatory markers, MCP-1 and ICAM-1 were remarkably higher in hyperlipidemic subjects compared to control. Correlation analyses demonstrated that Gla-Gas6 levels were inversely correlated with MCP-1 and ICAM-1 but positively with plasma VK in hyperlipidemic subjects but not in control. This suggests that boosting VK level might ameliorate the hyperlipidemia-associated inflammatory pathophysiology via augmenting Gla-Gas6. Further studies with high fat diet (HFD)-fed mice demonstrated that VK supplementation (1, 3, and 5 mu g/kg BW, 8 weeks) dose-dependently reduced both hepatic and plasma levels of MCP-1 and ICAM-1 while elevating that of Gla-Gas6 but not total Gas6 in HFD-fed mice. Cell culture studies with gamma-glutamyl carboxylase (enzyme causes VK-dependent carboxylation of Gas6) knockdown hepatocytes and monocytes dissected the direct role of Gla-Gas6 in inhibiting high palmitic acid (0.75 mM)-induced inflammation via arresting MCP-1/ICAM-1 mediated hepatocyte-monocyte adhesion. The present study demonstrated an important role of Gla-Gas6 in facilitating the prophylactic effect of VK against hyperlipidemia associated inflammation. (c) 2021 Elsevier Inc. All rights reserved.

Automated summary

This study found that Gla-Gas6 levels were lower in hyperlipidemic subjects and inversely correlated with pro-inflammatory markers MCP-1 and ICAM-1, while positively correlated with plasma VK levels. Increasing VK levels may mitigate hyperlipidemia-associated inflammation by enhancing Gla-Gas6. Animal studies showed that VK supplementation dose-dependently reduced inflammation markers and increased Gla-Gas6.