Vitamin C Regulates Lipid Metabolism Through PCSK9/LDLR And AMPK/LXR Signaling Pathway

Elevated low-density lipoprotein（LDL）-cholesterol and triglycerides in plasma is common of dyslipidemia,which is closely related to the development of cardiovascular diseases.Therefore,improving dyslipidemia can effectively prevent the occurrence of cardiovascular diseases.Proprotein convertase subtilisin/kexin 9（PCSK9）can bind to LDLR to make LDLR degradated intracellularly,resulting in suppressed LDL-cholesterol clearance from the circulation.Accordingly,inhibition of PCSK9 could decrease plasma LDL level efficiently.In addition,activation of liver X receptorα（LXRα）in the liver can induce lipid synthesis,leading to fatty liver and hypertriglyceridemia.Therefore,inhibiting the LXRαactivity can reduce the excessive synthesis of liver lipids.Vitamin C also known as ascorbic acid,is a water-soluble antioxidant.In addition to properties of antioxidation,ascorbicity and promoting collagen synthesis,it also has a positive effect on lipid profiles.However,little is known about the underlying mechanism of ascorbic acid-mediated lipid metabolism.Here,we determined if ascorbic acid can regulate expression of PCSK9,and whether the LXRαsignaling pathway is involved in the regulation of ascorbic acid on triglycerides.Vitamin C inhibits PCSK9 expression and promotes LDLR expression in hepatocytes.At cellular levels,ascorbic acid inhibited PCSK9 expression in Hep G2,Huh7 cells and mouse primary hepatocytes.Consequently,LDLR expression and cellular LDL uptake were enhanced.Mechanistically,ascorbic acid suppressed PCSK9expression in a forkhead box O3a（Fox O3a）-dependent manner.In addition,ascorbic acid increased LDLR transcription by regulating sterol regulatory element-binding protein 2（SREBP2）.Vitamin C regulates LDL-cholesterol metabolic homeostasis through PCSK9/LDLR signaling pathway.In vivo,administration of ascorbic acid reduced serum PCSK9 level and enhanced liver LDLR expression in C57BL/6J mice.In contrast,lack of ascorbic acid production in Gulo^-/-mice increased circulating PCSK9and LDL-cholesterol levels,and decreased liver LDLR expression.Moreover,ascorbic acid level was negatively correlated to PCSK9,total-and LDL-cholesterol levels in human serum samples.Vitamin C inhibits lipogenesis via activating AMPKαand inhibiting LXRα signaling pathway.In addition to affecting LDL-cholesterol metabolism through the PCSK9/LDLR signaling pathway,we indicate that ascorbic acid inhibits fatty acid synthase（FASN）,acetyl-Co A carboxylase 1（ACC1）and sterol-responsive element binding protein 1c（SREBP1c）expression.Consequently,ascorbic acid reduced triglycerides in hepatocytes.In vivo,administration of ascorbic acid reduced serum and liver triglyceride levels in high fat diet-fed mice.The free fatty acid（FFA）level in the liver was markedly reduced by ascorbic acid.Mechanistically,ascorbic acid inhibited lipid accumulation in hepatocytes,which was related to the reduction of LXRαnuclear translocation and AMPKαactivation.In summary,we identified reduction of PCSK9 expression and LDL-cholesterol level accompanied by increased LDLR expression as the novel activity of ascorbic acid.In addition,ascorbic acid inhibits the expression of lipid synthesis genes and reduces triglycerides levels by activating AMPKαand inhibiting LXRαsignaling pathway.We provided an underlying mechanism by which ascorbic acid ameliorates lipid profiles,and provided a theoretical basis for supplementing dietary ascorbic acid.