Gamma-glutamyl carboxylated Gas6 mediates the beneficial effect of vitamin K on lowering hyperlipidemia via regulating the AMPK/SREBP1/PPARα signaling cascade of lipid metabolism.

The present study for the first time aims to examine the hypothesis that circulating gamma-glutamyl carboxylated growth arrest specific protein 6 (Gla-Gas6) deficiency may be associated with hyperlipidemia and vitamin K (VK) supplementation may ameliorate the impaired lipid homeostasis via activating Gas6 protein. Subjects with hyperlipidemia (n=22) and age-matched healthy controls (n=19) were included in this study. Results showed that plasma levels of Gla-Gas6 protein and VK were significantly lower in hyperlipidemic subjects compared to control. Moreover, Gla-Gas6 levels were significantly and positively correlated with VK (P=.034, r=0.452) and negatively with triglyceride (P=.022, r=-0.485) and total cholesterol (P=.043, r=-0.435) in hyperlipidemic subjects, which suggest that VK supplementation may have a positive effect in activating Gas6 protein and thereby reducing the aberrant plasma lipid levels. Further studies with high-fat diet (HFD)-fed animal model of hyperlipidemia demonstrated that VK supplementation (5 μg/kg body weight, 8 weeks) reduced the plasma lipid levels, stimulated both the plasma levels and the hepatic protein expression of Gla-Gas6 protein, and regulated the AMPK/SREBP1/PPARα signaling pathways of hepatic lipid metabolism in HFD-fed mice. Moreover, by using palmitic acid (PA, 0.75 mM)-treated both control and GGCX knockdown hepatocytes, this study dissected the direct role of Gla-Gas6 in mediating the positive effect of VK on preventing the PA-induced impaired hepatic lipid metabolism via regulating AMPK/SREBP1/PPARα pathways. Combining all, the present study demonstrated the beneficial effect of VK supplementation in preventing the impaired lipid homeostasis via activating VK-dependent Gas6 protein.