13C asymmetry in blood glucose as a marker for oxidative stress in liver

血糖中的 13C 不对称性作为肝脏氧化应激的标志

• 批准号: 9288174
• 负责人: EUNSOOK JIN
• 金额: $ 27.67万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9288174
• 关键词: Acetaminophen; Acetylcysteine; Affect; Antioxidants; Biochemical; Biochemical Reaction; Blood; Blood Glucose; Blood specimen; Carbon; Chronic; Cirrhosis; Clinical; Data; Detection; Development; Disease; Disease Management; Dose; Enzymes; Event; Fatty Liver; Fatty acid glycerol esters; Gene Expression; Glucose; Glycerol; Goals; Hepatic; Hepatotoxicity; Homeostasis; Human; Ingestion; Intervention; Isotopes; Lipid Peroxidation; Lipid Peroxides; Liver; Liver Failure; Liver diseases; Malondialdehyde; Measurement; Measures; Metabolic Pathway; Methods; Modeling; Monitor; NADP; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Pathway; Patients; Pattern; Pentose Phosphate Cycle Pathway; Pentosephosphate Pathway; Perfusion; Pharmaceutical Preparations; Phase; Physiology; Pilot Projects; Play; Procedures; Production; Rattus; Reaction; Regulation; Rodent Model; Role; Stress; Technology; Testing; Therapeutic; Tracer; Transaldolase; Triglycerides; base; circulating biomarkers; diabetic; glucose production; human subject; in vivo; liver biopsy; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; public health relevance; response

DESCRIPTION (provided by applicant): Regulation of hepatic redox state plays a central role in normal physiology and high-impact diseases including non-alcoholic fatty liver disease and hepatotoxicity induced by many drugs. Liver biopsy is recommended for patients with those problems to monitor hepatic oxidative stress and other progress of the diseases, but it is invasive. There is a demand for a simple, less invasive method to monitor redox disruption in many hepatic diseases. It would benefit to develop a method to assess flux in key reactions involved in the response to oxidative stress and protection of the redox state of the liver. The pentose phosphate pathway (PPP) produces NADPH reducing equivalent that is essential for antioxidant defense and it has intricate interactions with hepatic glucose production. Recently we found that the liver given [U- 13C3]glycerol produced unique 13C asymmetry between carbons 1-3 and 4-6 of blood glucose, which was sensitive to the PPP and transaldolase activity. Transaldolase, a key enzyme in the non-oxidative phase of the PPP, is considered to have roles under oxidative stress. Here we hypothesize that the amounts of 13C glucose isotopomers produced and released from the liver given [U-13C3]glycerol are sensitive to hepatic oxidative stress. To test this, we will determine correlations in the following events: acetaminophen stressed or fatty liver -> hepatic oxidative stress -> altered hepatic PPP and transaldolase activity -> altered 13C asymmetry of glucose released from the liver. Both rodent models and human subjects with fatty liver will be studied to determine 13C asymmetry of glucose caused by chronic oxidative stress. We will determine if the asymmetry from patients with nonalcoholic steatohepatitis can be distinguished from simple steatosis. In addition, we will study rodent models of acetaminophen-induced hepatotoxicity and healthy subjects given therapeutic doses of acetaminophen if 13C asymmetry of glucose is sensitive to the drug. The results will be compared with gene expression data and standard methods for oxidative stress measurement. The overall procedures are simple: [U-13C3]glycerol ingestion, blood draw and blood glucose analysis by 13C NMR. Liver fat content in human subjects will be measured using 1H MRS. Our goal is to develop a simple method to identify and monitor hepatic oxidative stress by observing 13C asymmetry in blood glucose, which is readily determined from a single blood sample.

描述（由申请人提供）：肝脏氧化还原状态的调节在正常生理和高影响性疾病（包括非酒精性脂肪肝和许多药物诱导的肝毒性）中起着核心作用。肝活检可用于监测肝脏氧化应激及其他疾病的进展，但具有侵入性。需要一种简单、侵入性较小的方法来监测许多肝脏疾病中的氧化还原破坏。这将有利于开发一种方法来评估通量的关键反应参与的氧化应激反应和保护氧化还原状态的肝脏。戊糖磷酸途径（PPP）产生NADPH还原当量，这是抗氧化防御所必需的，它与肝脏葡萄糖产生有复杂的相互作用。最近，我们发现给予[U-1 - 3 C3]甘油的肝脏在血糖的碳1-3和4-6之间产生独特的1 - 3 C不对称性，其对PPP和转醛醇酶活性敏感。转醛醇酶是PPP非氧化相的关键酶，被认为在氧化应激下发挥作用。在此，我们假设给予[U-13 C3]甘油后，肝脏产生和释放的13 C葡萄糖同位素异构体的量对肝脏氧化应激敏感。为了测试这一点，我们将确定以下事件中的相关性：对乙酰氨基酚应激或脂肪肝->肝氧化应激->改变的肝PPP和转醛醇酶活性->改变的从肝释放的葡萄糖的13 C不对称性。将研究具有脂肪肝的啮齿动物模型和人类受试者以确定由慢性氧化应激引起的葡萄糖的13 C不对称性。我们将确定非酒精性脂肪性肝炎患者的不对称性是否可以与单纯性脂肪变性区分开来。此外，我们将研究对乙酰氨基酚诱导的肝毒性的啮齿动物模型和给予治疗剂量对乙酰氨基酚的健康受试者，如果葡萄糖的13 C不对称性对药物敏感。将结果与基因表达数据和氧化应激测量的标准方法进行比较。总体程序很简单：[U-13 C3]甘油摄入、抽血和通过13 C NMR进行血糖分析。人类受试者的肝脏脂肪含量将使用1H MRS测量。我们的目标是开发一种简单的方法，通过观察血糖中的13 C不对称性来识别和监测肝脏氧化应激，这很容易从单个血液样本中确定。