Extra-hepatic postprandial metabolism of dietary fructose

膳食果糖的肝外餐后代谢

• 批准号: 10614587
• 负责人: Grace Marie Jones
• 金额: $ 32.05万
• 依托单位: TOURO UNIVERSITY OF CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614587
• 关键词: Acetates; Address; Affect; Apolipoproteins; Apolipoproteins B; Apolipoproteins C; Apoproteins; Appearance; Beds; Biological Assay; Blood Circulation; Carbon Dioxide; Cardiovascular Diseases; Chronic Disease; Chylomicrons; Circulation; Consumption; Data; Diet; Dose; Enrollment; Enzyme-Linked Immunosorbent Assay; Extrahepatic; Fatty acid glycerol esters; Foundations; Fructose; Gluconeogenesis; Glucose; Glycogen; Health Policy; Hepatic; Human; Hyperlipidemia; Impairment; Indirect Calorimetry; Ingestion; Insulin Resistance; Intake; Intestines; Intravenous; Intravenous infusion procedures; Isotopes; Label; Laboratories; Lipids; Lipoproteins; Liver; Mass Fragmentography; Mass Spectrum Analysis; Measurement; Measures; Metabolic; Metabolism; Methods; Mission; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Oral; Oral Administration; Parents; Peripheral; Physiological; Plasma; Population; Prediabetes syndrome; Process; Production; Public Health; Publishing; Reporting; Risk; Role; Route; Site; Small Intestines; Stable Isotope Labeling; Techniques; Time; Tissues; Tracer; Triglycerides; Very low density lipoprotein; apolipoprotein C-III; cardiovascular disorder risk; comparison control; dietary; feeding; hepatic gluconeogenesis; interest; lipid biosynthesis; liver metabolism; non-alcoholic fatty liver disease; novel; oxidation; parent grant; prevent; response; stable isotope; sugar

High sugar consumption, and more specifically fructose intake, leads to lipid profiles associated with increased risk of type 2 diabetes (T2D), cardiovascular disease (CVD), and non-alcoholic fatty liver disease. The underlying metabolic mechanisms leading to these conditions remain largely unknown. The parent study for this proposal, R01DK116033, focuses on the role and metabolic fates of fructose in the liver, which historically was considered the main tissue handling fructose. This proposal takes into account our preliminary data supporting a major role of non-hepatic tissues as sites of fructose metabolism, and of apolipoprotein clearance factors influencing postprandial lipid profiles. We address three questions related to non-hepatic fructose metabolism using high- and low-fructose meals in pre-diabetic and control subjects enrolled in the parent trial. Our first question regards the role of the small intestine in fructose metabolism; specifically the conversion of fructose to fat by de novo lipogenesis (DNL) and the composition of apolipoproteins in chylomicrons (CM), namely apoCIII, and apoB, and their relative contribution to postprandial hyperlipidemia. We developed an immunoaffinity method to isolate CM that transport the fat packaged in the small intestine. This will allow us to quantify, for the first time, intestinal DNL and the apolipoprotein composition of CM without contamination from fat made in the liver and transported by very-low density lipoproteins (VLDL). Our second question addresses the amount of fructose that escapes intestinal and hepatic metabolism and appears in the circulation, thereby becoming available to other tissues. For this aim, we will use a recently published dual stable isotope method to measure plasma fructose levels. Additionally, this method will allow us to explore, for the first time, intestinal gluconeogenesis in humans. For our third question, we will measure how much fructose is used as fuel by determining the amount of fructose that is completely oxidized to produce labeled 13CO2. Recent studies have suggested that oxidation is another major route of fructose metabolism. The administration of oral and intravenous stable isotopes in 18 pre-diabetic and 18 control subjects enrolled in the parent trial and the application of a technique to fractionate TRL allows for the quantification of CM and VLDL apolipoproteins and intestinal- and hepatic- DNL, along with measurements of fructose in the peripheral circulation, estimation of intestinal gluconeogenesis, and fructose oxidation. By measuring DNL, clearance factors, circulating fructose, and fructose oxidation in conjunction with the measurements of the parent study (hepatic gluconeogenesis, TRL-DNL and glycogen storage), we will have a more complete characterization of fructose metabolism and answer longstanding questions regarding the fates of fructose in two distinct populations. Importantly, we will demonstrate how extra-hepatic fructose metabolism contributes to T2D and CVD risk.

高糖消耗，更具体地说是果糖摄入，导致与2型糖尿病风险增加（T2D），心血管疾病（CVD）和非酒精性脂肪肝疾病有关的脂质谱。导致这些疾病的基本代谢机制在很大程度上尚不清楚。该提案的父母研究R01DK116033着重于肝脏中果糖的作用和代谢命运，从历史上看，果糖在历史上被认为是主要的组织处理果糖。该建议考虑了我们的初步数据，该数据支持非肝脏组织作为果糖代谢部位的主要作用，以及影响餐后脂质剖面的载脂蛋白清除因子。我们在父母试验的糖尿病前和对照组中使用高果糖和低果糖粉与非肝果糖代谢有关的三个问题。我们的第一个问题是小肠在果糖代谢中的作用。具体而言，从头脂肪生成（DNL）（DNL）将果糖转化为脂肪，以及在乳糜微粒（CM）中的载脂蛋白的组成，即apociii和Apob，及其对植物高脂高脂的相对贡献。我们开发了一种免疫亲和力方法来分离CM，该CM运输了包装在小肠中的脂肪。这将使我们能够首次量化肠道DNL和CM的载脂蛋白组成，而不会因肝脏中脂肪而受到污染，并通过非常低的密度脂蛋白（VLDL）运输。我们的第二个问题介绍了逃避肠道和肝代谢的果糖的数量，并出现在循环中，从而成为其他组织。为此，我们将使用最近发布的双重稳定同位素方法来测量血浆果糖水平。此外，这种方法将使我们能够在人类中首次探索肠糖异生。对于我们的第三个问题，我们将通过确定完全氧化以产生标记为13CO2的果糖的量来测量多少果糖用作燃料。最近的研究表明，氧化是果糖代谢的另一种主要途径。在父母试验中注册的18个糖尿病前和18个对照对象的口服和静脉注射稳定同位素的给药，并且将技术应用于分级TRL，可以定量CM和VLDL载脂蛋白以及肠道和肠道和肝DNL，以及果糖在周围循环中的测量，肠糖异生的估计和果糖氧化。通过测量DNL，清除因子，循环果糖和果糖氧化以及父母研究的测量（肝糖生成，TRL-DNL和糖原储存），我们将对果糖代谢和回答有关果糖代谢的更完整的特征两个不同种群中果糖的命运。重要的是，我们将证明肝外果糖代谢如何对T2D和CVD风险贡献。