Metabolomic and Lipidomic Investigation of Hyperlipidemia and Acute Coronary Syndrome

Abstract

Metabolomics, the study of metabolome, is interdiscipilinary science investigating metabolic response to genetic or environmental pertubations. It can be applied to understand systemic interaction of metabolites in biological networks, to evaluate drug efficacy and toxicity, and to discover novel biomarkers for human diseases. In this study, metabolomics approach was used to investigate hyperlipidemia and acute coronary syndrome. Lipidomics study, a subset of metabolomics field, was also applied to the present study as lipids are critical metabolites which play plenty of roles to hyperlipidemia and acute coronary syndrome. Particularly, lipidomic platform was optimized in terms of sample preparation and instrumental condition. Finally, both metabolomic and lipidomic study were conducted using ultra performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). First, metabolomic profiles after rosuvastatin administration in healthy volunteer group and hyperlipidemic patients were evaluated to find out rosuvastatin effect on endogenous metabolism in hyperlipidemia. Using UPLC-QTOF-MS data, several kinds of metabolites including amino acids, lipids, acylcarnitines and bile acids were detected from plasma and urine samples of healthy volunteers and hyperlipidemic patients. Among these metabolites lysophosphatidylcholines, fatty acids, 3-methylglutarylcarnitine increased significantly, however, phosphatidylcholines, L-carnitine and acylcarnitines significantly decreased after rosuvastatin administration. Those changes were highly correlated to rosuvastatin drug response of decrease LDL, cholesterol and ApoB. Based on metabolic profile of rosuvastatin reponse, the effect of rosuvastatin on endogenous metabolic pathway was suggested, which can be possible mechanistic explanation of rosuvastatin-induced myopathy. Secondly, metabolomics study was performed using serum sample of healthy subjects and patients with unstable angina and acute myocardial infarction to discover diagnostic biomarker of acute coronary syndrome. After analyzing samples using UPLC-QTOF-MS, twenty-one metabolites were identified, and among them sixteen metabolites including lysophosphaidylcholines, fatty acids and amino acids were applied to receiver operating characteristic (ROC) analysis. Multivariate ROC model using sixteen metabolites demonstrated higher accuracy, sensitivity and specificity compared to univariate ROC curve of single metabolite. As a result, a diagnostic platform using multi-biomarker was developed for acute coronary syndrome through multivariable ROC analysis.;대사체학은 대사체를 연구하는 학문으로, 유전적 또는 환경적인 미세한 변화에 대한 대사 반응을 연구하는 학문이다. 대사체학은 생체 네트워크에서 대사체 간 상호작용을 총괄적으로 이해하고, 약물 효능과 독성을 평가하고, 질병을 진단하는 새로운 바이오마커 발굴에 응용될 수 있다. 이 논문에서는 대사체학 접근법을 활용하여 고지혈증에서 내인성 대사에 미치는 로수바스타틴의 효과를 알아보았고, 급성 관상동맥 질환을 진단할 수 있는 다중 바이오마커를 발굴하였다. 대사체학 분야 중 하나인 지질대사체학 또한 이 논문에서 다루어졌는데, 이것은 지질이 고질혈증과 급성 관상동맥 질환에 다양한 역할을 하는 중요한 대사체이기 때문이다. 특히 지질대사체 연구를 위해서 시료 전처리 과정과 기기 분석 조건을 이 논문에서 최적화하였다. 결과적으로, 이 논문에서는 초고성능 액체 크로마토그래피-질량분석기를 이용하여 대사체학 및 지질대사체학 연구를 수행하였다. 그 결과, 로수바스타틴 투여로 인해 내인성 대사체인 라이소포스파티딜콜린, 포스파티딜콜린, 지방산, 아실카르니틴이 변화한다는 대사체 프로파일리에 성공하여고, 내인성 대사 과정에 로수바스타틴이 미치는 영향과 관련된 가능한 대사 기전을 제시하였다. 또한, 다변량 수신자 조작 특성 곡선 모델을 사용하여 아미노산, 지질을 포함하는 다중 바이오마커 진단 플랫폼을 개발하였고 급성 관상동맥 질환 진단 기술 개발에 기여하였다.