Metabonomics Strategy For The Discovery Of Novel Biomarkers Of Hyperlipidemia And Investigation On The Pharmacological Mechanism Of FTZ Treatment

Background Present studies about hyperlipidemia often based on molecular biological investigation,which focused on limited biochemical and histopathological indicators but ignored global understanding of the pantasomatous metabolism changes.Existing lipid-lowering drugs were mainly western medicine.A single class of lipid-lowering drugs only corresponded to treat the specific classification of hyperlipidemia.Qualitative and semiquantitative metabolomics methods could be used to analyze the physiological and pathological changes.It helps us to explore the diseases and the mechanism of drug treatment deeply.The metabolic profiles of different types of hyperlipidemia could provide a deeper understanding of hyperlipidemia and the discovery of novel biomarkers for us.The metabolomic could further reveal the efficacy mechanism of Fufang Zhen Zhu Tiaozhi Fang(FTZ)in hyperlipidemia mice.Purposes The novel biomarkers in plasma of hyperlipidemia patients were discovered and the effects and mechanism of FTZ on hyperlipidemia mice were explored by metabolomics methods.Methods This study was divided into two parts included clinical research and animal research.Different types of hyperlipidemia patients were divided into five groups according to the classification standard.Their plasma were used for metabolomics analysis to discover the novel biomarkers of hyperlipidemia.In animal experiments,male C57 mice were used as research subjects to establish a hyperlipidemia model with high-fat diet.The model of hyperlipidemia mice and the efficacy mechanism of FTZ were evaluated by metabolomics techniques.Results 1.Efficacy of medicine FTZ could reduce the glucose and lipid levels of hyperlipidemia mice significantly.2.Metabolomics results 2.1 Plasma metabolomics results in patients with hyperlipidemia It has been found that I-urobilin,leukotriene C4 and other metabolites are potential biomarkers in plasma of patients with hyperlipidemia.The pathogenesis of hyperlipidemia might be related to the disorder of the pathways,which included glycerophospholipid metabolism,sphingolipid metabolism,dicarboxylic acid metabolism,and folic acid biosynthesis.Lithocholic acid taurine conjugate and N1-(5-Phospho-D-ribosyl)-ATP are common biomarkers for different types of hyperlipidemia.The 2-Hydroxy-3-keto-5-methylthiopentenyl-1-phosphate as the specific biomarker for hypercholesterolemia;15-keto-Prostaglandin E2 and PI(18:0/22:4(10Z,13 Z,16Z,19Z))as the specific biomarkers for combined hyperlipidemia familial;tartronate semialdehyde and 2,5-Diamino-6-(5’-triphosphoryl-3)’,4’-trihydroxy-2’-oxopentyl)-amino-4-oxopyrimidine as the specific biomarkers for high-low-density lipoproteinemia group were determined.No specific differentially expressed metabolites were discoverd in the high triglyceride group yet.2.2 The evaluation of hyperlipidemia animal model The results showed that the metabolites such as Lyso PC(18:1(9Z)),PIP(18:0/20:3(8Z,11 Z,14Z)),arachidonic acid,linoleic acid,and 9-HETE and the pathways included linoleic acid metabolism,arachidonic acid metabolism and glycerophospholipid metabolism were all important evaluation indexes for hyperlipidemia animal models.2.3 Metabolomic analysis of FTZ intervention Differentially expressed metabolites such as sphingosine,phytosphingosine,and PE(16:1(9Z)/24:1(15Z))are biomarkers of FTZ for improving glucose and lipid metabolism disorders.Pathway analysis showed that the effect and mechanism of FTZ might be associated with sphingolipid metabolism,GPI-anchor biosynthesis and glycerophospholipid metabolism.Conclusion Different types of hyperlipidemia not only had common biomarkers,but also had specific biomarkers except hypertriglyceridemia.The pathogenesis of hyperlipidemia might be involved in glycerophospholipid metabolism,folic acid biosynthesis,and sphingolipid metabolism disorders.Lyso PC(18:1(9Z)),PIP(18:0/20:3(8Z,11 Z,14Z)),arachidonic acid,linoleic acid,and 9-HETE were all important evaluation indexes for hyperlipidemia animal models.FTZ could improve the glucose and lipid metabolism disorders effectively,which might relate to the pathways such as sphingolipid metabolism,GPI-anchor biosynthesis and glycerophospholipid metabolism.Metabolomics is a good research method for deep understanding of hyperlipidemia and exploring the intervention mechanism of lipid-lowering traditional Chinese medicines.