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.

高糖摄入量，更具体地说是果糖摄入量，会导致血脂异常，与 2 型糖尿病 (T2D)、心血管疾病 (CVD) 和非酒精性脂肪肝风险增加相关。导致这些病症的潜在代谢机制在很大程度上仍然未知。该提案的母研究 R01DK116033 重点关注果糖在肝脏中的作用和代谢命运，肝脏历来被认为是处理果糖的主要组织。该提议考虑到了我们的初步数据，这些数据支持非肝组织作为果糖代谢场所的主要作用，以及影响餐后血脂状况的载脂蛋白清除因子。我们在参加母试验的糖尿病前期和对照受试者中使用高果糖和低果糖膳食解决了与非肝果糖代谢相关的三个问题。我们的第一个问题是关于小肠在果糖代谢中的作用；特别是通过从头脂肪生成 (DNL) 将果糖转化为脂肪，以及乳糜微粒 (CM) 中载脂蛋白的组成，即 apoCIII 和 apoB，以及它们对餐后高脂血症的相对贡献。我们开发了一种免疫亲和方法来分离运输小肠中包装的脂肪的 CM。这将使我们能够首次量化肠道 DNL 和 CM 的载脂蛋白组成，而不会受到肝脏产生并由极低密度脂蛋白 (VLDL) 运输的脂肪污染。我们的第二个问题涉及逃逸肠道和肝脏代谢并出现在循环中，从而可供其他组织利用的果糖量。为此，我们将使用最近发布的双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首次探索人类肠道糖异生。对于第三个问题，我们将通过确定完全氧化产生标记的 13CO2 的果糖量来测量作为燃料使用的果糖量。最近的研究表明氧化是果糖代谢的另一个主要途径。对参加母试验的 18 名糖尿病前期受试者和 18 名对照受试者进行口服和静脉注射稳定同位素，并应用 TRL 分级技术，可以对 CM 和 VLDL 载脂蛋白以及肠道和肝脏 DNL 进行定量，以及外周循环中果糖的测量、肠道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，并结合母研究的测量（肝糖异生、TRL-DNL 和糖原储存），我们将对果糖代谢有更完整的表征，并回答有关果糖代谢的长期问题。果糖在两个不同人群中的命运。重要的是，我们将证明肝外果糖代谢如何导致 T2D 和 CVD 风险。