Abstract
Objectives
Vitamin K (VK), an important antihemorrhagic vitamin has attracted scientific attention recently due to its diverse physiological activities beyond hemostasis. Present study for the first time systematically examined the hypothesis that circulating VK deficiency might be linked with hyperlipidemia-associated inflammatory pathophysiology and VK supplementation may ameliorate the hepatic inflammation via activating growth arrest specific 6 (Gas6) protein, an important member of the coagulation-unrelated vitamin K-dependent proteins.
Methods
Subjects with hyperlipidemia (n = 22) and age-matched healthy controls (n = 19) attending the institute clinical center were included in this study. High fat diet (HFD)-fed male albino mice model was used for in vivo studies. High palmitic acid (PA, 0.75 mM)-treated and GGCX knockdown monocytes and hepatocytes were employed for in vitro studies. All data were analyzed using Sigma Stat statistical software.
Results
Plasma levels of VK and Gla-Gas6 were significantly lower and intercellular adhesion molecule-1 (ICAM-1) was remarkably higher in hyperlipidemic subjects compared to control. Correlation studies showed that both circulatory Gla-Gas6 and VK levels were significantly and inversely correlated with ICAM-1. Interestingly, Gla-Gas6 was positively correlated with plasma VK, which suggests that VK supplementation may ameliorate the hyperlipidemia-induced inflammation via activating Gas6. Further studies with HFD-fed hyperlipidemic animals demonstrated that VK supplementation dose-dependently reduced the hepatic expression of pro-inflammatory cytokines while elevating the plasma level of Gla-Gas6 in HFD-fed mice. In vitro studies showed that VK supplementation prevented the high PA-induced hepatic inflammation in a dose-dependent manner. Furthermore, the knockdown study established the direct role of Gla-Gas6 in mediating the positive effect of VK on the management of PA-induced hepatic inflammation.
Conclusions
Combining all, the present study demonstrated the beneficial effect of VK supplementation on the management of hyperlipidemia-associated inflammatory events via activating VK-dependent Gas6 protein.
Funding Sources
Junior research fellowship to JB & Ramalingaswami fellowship to PM by DBT, Govt. of India.