| 摘要: | 代謝症候群(metabolic syndrome)又稱作胰島素抗拒症候群(insulin resistance syndrome)，是一種多面向的複雜疾病。罹患代謝症候群的病人會增加罹患糖尿病與粥狀動脈硬化相關之心血管疾病的風險。然而，足以充分反映代謝症候群病理機轉的血液或尿液生物標記(biomarker)，至今仍付之闕如。本研究即擬以代謝體學為平台，藉此探尋代謝症候群可能之生物標記。
經由綜觀尿液代謝物分析所形成之代謝體學(metabolomics)，得反映體內代謝物最終的變化，所以有其臨床檢體採集的便利性與實用性。因此，本研究以代謝體學的實驗設計，藉由高效能液相層析儀併飛行時間質譜 (high-performance liquid chromatography-time of flight mass spectrometry)，分析代謝症候群相關診斷定義(包括過重、血壓偏高、血脂異常或葡萄糖耐受不良)之各類受試者，以及餵食高果糖與高脂肪以模擬代謝症候群之Sprague–Dawley大鼠的尿液代謝物，藉此探尋足以充分反映代謝症候群至動脈硬化之病理機轉的生物標記。
本研究發現，在所有分析之尿液代謝物中，菸鹼尿酸(nicotinuric acid)足以反映代謝症候群的病理機轉特性，並且菸鹼尿酸的尿液濃度與受試者的身體質量指數(body mass index)、血壓、總膽固醇、低密度膽固醇、三酸甘油脂與高敏感度C-反應蛋白(high sensitivity C-reactive protein)呈現正相關性，卻與高密度脂蛋白呈現負相關性。
最終，本研究提出菸鹼尿酸反映動脈硬化進展之代謝途徑假說。菸鹼尿酸作為甜菜鹼(betaine)、甘胺酸(glycine)與色胺酸(tryptophan)代謝的最終產物，不僅在胰島素抗拒性與血脂異常方面，足以表現菸草醯胺腺嘌呤二核苷酸磷酸鹽(NADP+/NADPH)在合成脂肪酸的氧化還原反應，此外，也在粒線體、細胞質與內質體中各種脫氫反應(dehydrogenase reactions)中扮演輔酶角色，並與膽鹼(choline)透過腸道菌群(gut microbiota)之代謝造成粥狀動脈硬化的最新理論相互呼應。藉由本研究對於菸鹼尿酸代謝途徑的探討，有助於進一步釐清代謝症候群至動脈硬化進展過程中的病理生理機轉。
The metabolic syndrome, also termed the insulin resistance syndrome, is a multiplex disorder and puts patients on the road to type 2 diabetes and atherosclerotic cardiovascular diseases. However, a surrogate biomarker in plasma or urine in fully reflecting features of metabolic syndrome has not been explored. The aim of this study is to find potential biomarkers for metabolic syndrome through metabolomics approach.
Urine metabolomics has potential utility in metabolic profiling because urine metabolites analysis reflects global outflux of metabolic change. Accordingly, This study randomly selected subjects with parameters of metabolic syndrome (overweight, dyslipidemia, hypertension or impaired glucose tolerance) and chose Sprague–Dawley rats fed with high-fructose and high-lipid diet to mimic metabolic syndrome. We took a metabolomics approach to analyze the metabolites of urine by high-performance liquid chromatography-time of flight mass spectrometry and elicit potential biomarkers to picture road from metabolic syndrome to atherosclerosis.
Moreover, among the analyzed metabolites, this study also found that urinary nicotinuric acid level could reflect the pathologic mechanism of metabolic syndrome and positively correlated with body mass index, blood pressure, total cholesterol, low-density lipoprotein cholesterol, triacylglycerol and high sensitivity C-reactive protein, but negatively correlated with high-density lipoprotein cholesterol.
Finally, this study also proposed the hypothesis about the metabolic pathway to atherosclerosis via nicotinuric acid. As the end product from betaine, glycine and tryptophan, nicotinuric acid is compatible with the latest finding of atherosclerosis formation from choline via gut microbiota. Moreover, the nicotinuric acid levels in urine reveal the change of NADP+/NADPH. NADP+/NADPH are the coenzymes for oxidation-reduction reactions of fatty acid synthesis and participation in various dehydrogenase reactions of mitochondrion, cytoplasm, and endoplasmic reticulum, in the process of insulin resistance and dyslipidemia. Further interpretation of metabolic process of nicotinuric acid may provide a pathophysiologic basis for understanding the progression from metabolic syndrome to atherosclerosis. |
