The effect of fructose on human hepatocyte-adipocyte cellular crosstalk and metabolic health

果糖对人肝细胞-脂肪细胞细胞串扰和代谢健康的影响

• 批准号: BB/N015665/1
• 负责人: Leanne Hodson
• 金额: $ 67.22万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN015665%2F1
• 关键词: effect; fructose; human; hepatocyte; adipocyte

People are often confused about the sugars in their diet and ask questions such as:Isn't fructose a fruit sugar? If fructose is so bad for me should I be eating less fruit? I've been told soft drinks and sweets are bad for me, why is this?Fructose is the major fruit sugar; however it has unfavourable effects on health when consumed in excess through the consumption of products rich in 'added' sugars such as sweets and soft-drinks, rather than consumption of fruit. As the consumption of these products has increased over time, it has been suggested that added fructose in those products may directly contribute to the growing rates of obesity and obesity-related diseases such as type 2 diabetes and heart disease. As humans typically consume fructose in combination with glucose; we would like to understand how these sugars affect the function of two organs in the human body which play important roles in maintaining our health; adipose tissue and the liver. We would like to understand how adipose tissue and liver process fructose and whether elevated levels of fructose cause changes in function of the individual cells that make up these organs. We are able to investigate both aspects, firstly, by doing studies in healthy human participants and secondly, by using cells grown in the laboratory that have been donated by human volunteers.To understand whether having too much sugary food in our diets affects our health as a result of changes in normal adipose tissue and liver function we will study healthy people before and after they have altered their diet to include more foods that contain large amounts of fructose with glucose (e.g. soft-drinks). To determine the effect of having too much sugary food on adipose tissue and liver metabolism we will use specially labelled molecules (stable-isotopes), which have the equivalent of a GPS (global positioning signal) tag attached. The stable-isotopes will be eaten as part of a test meal and infused directly into the bloodstream of the participants. By taking regular blood samples over the course of the study day, we can then use techniques to detect the "GPS" signal in the blood to determine if adipose tissue and liver function have been changed by the sugary diet. We will use a specialised technique (called arterio-venous difference) to study adipose tissue on the human body that is on the tummy (abdominal) and on the upper leg/buttock (gluteofemoral). We will study these two fat depots as there is evidence to suggest fat from these sites has different functions and can have opposite effects on human health.To look in closer detail at the pathways involved in processing fructose and changes in cell function caused by fructose we will isolate individual cells from human adipose tissue (called preadipocytes) and human liver (called hepatocytes). The cells will be exposed to varying amounts of fructose and glucose and we will measure changes in the health and function of the cells. In addition to using stable-isotopes to trace the metabolism of fructose and glucose, we can also look at markers of cell death, the ability of the cells to make and store fat, the production of energy and whether normal signalling pathways are disrupted. We will also measure signals released by the adipocytes and hepatocytes when they are exposed to fructose; identifying these signals will provide further information of cell function. We will then investigate whether these signals are used as a form of communication between the adipose tissue and liver.These studies are important because, at present, there is much confusion surrounding the effects sugary foods have on human health. Our studies will provide important answers to how fructose is processed in the human body and what effects elevated fructose consumption has on human health. We hope that our findings will be used to provide information toward nutritional advice to reduce the risk of developing obesity and obesity-associated diseases.

人们经常对饮食中的糖感到困惑，并会问这样的问题：果糖不是水果糖吗？如果果糖对我这么不好，我应该少吃水果吗？有人告诉我软饮料和甜食对我有害，这是为什么？果糖是主要的水果糖；然而，如果过量食用富含添加糖的产品，如糖果和软饮料，而不是水果，它会对健康产生不利影响。由于这些产品的消费量随着时间的推移而增加，有人认为，在这些产品中添加果糖可能直接导致肥胖率和肥胖相关疾病(如2型糖尿病和心脏病)的增加。由于人类通常同时摄入果糖和葡萄糖，我们想了解这些糖如何影响人体两个器官的功能，这两个器官在维持我们的健康方面发挥着重要作用：脂肪组织和肝脏。我们想了解脂肪组织和肝脏是如何处理果糖的，以及果糖水平升高是否会导致组成这些器官的单个细胞的功能发生变化。我们能够研究这两个方面，首先，通过在健康的人类参与者身上进行研究，其次，通过使用由人类志愿者捐赠的实验室培养的细胞。为了了解饮食中过多的含糖食物是否会由于正常脂肪组织和肝功能的变化而影响我们的健康，我们将研究健康的人在改变饮食之前和之后，包括更多含有大量果糖和葡萄糖的食物(例如软饮料)。为了确定摄入过多含糖食物对脂肪组织和肝脏新陈代谢的影响，我们将使用专门标记的分子(稳定同位素)，这种分子相当于附加了GPS(全球定位信号)标签。稳定同位素将作为测试餐的一部分被吃掉，并直接注入参与者的血液中。通过在一天的研究过程中定期采集血液样本，我们可以使用技术来检测血液中的“GPS”信号，以确定脂肪组织和肝功能是否因含糖饮食而改变。我们将使用一种专门的技术(称为动静脉差异)来研究人体腹部(腹部)和大腿/臀部(臀部)的脂肪组织。我们将研究这两个脂肪库，因为有证据表明，来自这两个部位的脂肪具有不同的功能，可能对人类健康产生相反的影响。为了更详细地了解加工果糖的途径以及果糖引起的细胞功能变化，我们将从人类脂肪组织(称为前脂肪细胞)和人类肝脏(称为肝细胞)中分离单个细胞。这些细胞将暴露在不同数量的果糖和葡萄糖中，我们将测量细胞健康和功能的变化。除了使用稳定的同位素来追踪果糖和葡萄糖的新陈代谢，我们还可以观察细胞死亡的标志，细胞制造和储存脂肪的能力，能量的产生，以及正常的信号通路是否被破坏。我们还将测量脂肪细胞和肝细胞在接触果糖时释放的信号；识别这些信号将提供细胞功能的进一步信息。然后我们将调查这些信号是否被用作脂肪组织和肝脏之间的一种交流形式。这些研究是重要的，因为目前关于含糖食物对人类健康的影响有很多混乱。我们的研究将为果糖在人体内是如何处理的，以及增加果糖摄入量对人类健康有什么影响提供重要的答案。我们希望我们的发现将被用来为营养建议提供信息，以降低患肥胖症和肥胖相关疾病的风险。

项目成果

MLX plays a key role in lipid and glucose metabolism in humans: Evidence from in vitro and in vivo studies.

• DOI: 10.1016/j.metabol.2023.155563
• 发表时间: 2023-07
• 期刊: METABOLISM-CLINICAL AND EXPERIMENTAL
• 影响因子: 9.8
• 作者: Nagarajan, Shilpa R.;Livingstone, Eilidh J.;Monfeuga, Thomas;Lewis, Lara C.;Ali, Shahul Hameed Liyakath;Chandran, Anandhakumar;Dearlove, David J.;Neville, Matt J.;Chen, Lingyan;Maroteau, Cyrielle;Ruby, Maxwell A.;Hodson, Leanne
• 通讯作者: Hodson, Leanne

Report of a member-led meeting: how stable isotope techniques can enhance human nutrition research

成员主导的会议报告：稳定同位素技术如何加强人类营养研究

• DOI: 10.1017/s0029665120007016
• 发表时间: 2020
• 期刊: Proceedings of the Nutrition Society
• 影响因子: 7
• 作者: Fielding B

Determining the temporal, dose, and composition effects of nutritional substrates in an in vitro model of intrahepatocellular triglyceride accumulation.

• DOI: 10.14814/phy2.15463
• 发表时间: 2022-10
• 期刊: Physiological reports
• 影响因子: 2.5

Using total plasma triacylglycerol to assess hepatic de novo lipogenesis as an alternative to VLDL triacylglycerol.

使用总血浆三酰甘油来评估肝脏从头脂肪生成，作为 VLDL 三酰甘油的替代品。

• DOI: 10.1080/03009734.2020.1739789
• 发表时间: 2020
• 期刊: Upsala journal of medical sciences
• 影响因子: 3.4
• 作者: Hodson L

An optimised protocol for the investigation of insulin signalling in a human cell culture model of adipogenesis.

• DOI: 10.1080/21623945.2023.2179339
• 发表时间: 2023-12
• 期刊: ADIPOCYTE
• 影响因子: 3.3
• 作者: Gamwell, Jonathan M.;Paphiti, Keanu;Hodson, Leanne;Karpe, Fredrik;Pinnick, Katherine E.;Todorcevic, Marijana
• 通讯作者: Todorcevic, Marijana