Medium Chain Triglycerides and Ketogenesis

背景：中等脂肪酸链天然地以中链甘油三酯(MCT)的形式存在，可在椰子油和棕榈油中发现。MCT有不同的形式，可以在柜台上购买作为膳食补充剂(MCT油)。与其他脂肪酸不同，MCT提供即时能量，因为它们能够非常迅速地穿过双重线粒体膜，从而产生酮体(Kb)。有趣的是，许多研究表明，MCT补充剂增加了循环中的KB，并提高了运动成绩。然而，MCT的生物学作用以及MCT促进酮体生成(酮的发生)的机制还相对较少。因此，这项建议的主要目的是阐明补充MCT促进肝中酮的生成，从而增强肝脏线粒体功能的机制。 假设：我们假设MCT的补充通过增加生酮酶线粒体3-羟甲基戊二酰辅酶A合成酶(HMGCS2)的命运来增加循环KB，从而改善肝脏线粒体的功能。 方法：我们将利用一些细胞培养和动物方法来揭示MCT补充如何增加肝脏中KB的产生率。这包括用不同形式和浓度的MCT培养和处理肝细胞系(HepG2)，并评估酮生成酶和肝脏线粒体功能。此外，我们将让小鼠摄入富含MCT的食物12周，以确定MCT治疗是否增加了循环KB，增强了生酮途径(例如HMGCS2)，并通过肝脏提取物的mRNA/蛋白质表达谱来确定肝脏线粒体的功能。此外，能量消耗和能量底物偏好将通过间接量热法测量确定接受MCT丰富饮食的小鼠的能量消耗和能量底物偏好。 目的：这项研究计划将包括两个具体目标：(1)确定MCT治疗后肝脏中的生酮酶(HMGCS2)是否增加，以及(2)评估MCT治疗是否增加了肝脏线粒体功能。在目标1中，我们将不同形式和浓度的MCT处理培养的HepG2细胞，并研究生酮代谢途径的mRNA/蛋白质表达谱。此外，我们将测量高MCT饮食小鼠的循环KB，并通过间接量热法评估它们的全身耗氧率和呼吸交换率。在目标2中，我们将评估与线粒体功能有关的一些关键因素。 影响：我们的发现将深入了解补充MCT提高酮体生成率和肝脏线粒体功能的机制。此外，这项研究计划的结果也为那些将MCT作为非处方药营养膳食补充剂来增加KB的制造商提供了重要的见解。

Background: Medium fatty acids chain occur naturally as medium chain triglycerides (MCT) and can be found in coconut and palm oils. MCT have different forms and can be purchased over the counter as a dietary supplement (MCT oil). Unlike other fatty acid, MCT provide immediate energy because they are able to cross the double mitochondrial membrane very rapidly, and this results in the production of ketone bodies (KB). Of interest, many studies have shown that MCT supplements rise circulating KB and enhance athletic performance. However, the biological actions of MCT, and the mechanisms by which MCT may enhance ketone body production (Ketogenesis) have been relatively understudied. Hence, the major aims of this proposal are to elucidate the mechanisms by which MCT supplement increases ketogenesis in liver, and subsequently this will enhance liver mitochondrial function. Hypothesis: We hypothesize that MCT supplement increases circulation KB by augmenting the fate committing ketogenic enzyme mitochondrial 3-hydroxymethylglutaryl-CoA synthase (HMGCS2), as a result this will improve hepatic mitochondrial function. Methodology: We will utilize a number of cell culture and animal approaches to reveal how MCT supplement augment KB production rates in the liver. This includes culturing and treating liver cell line (HepG2) with different forms and concentrations of MCT, and assessing the ketogenesis enzymes and hepatic mitochondrial function. Furthermore, we will subject mice to MCT-rich diet for 12 weeks to determine whether MCT treatment increases circulating KB, enhances ketogenic pathway (e.g. HMGCS2) and hepatic mitochondrial function via mRNA/protein expression profiling of liver extracts. Moreover, energy expenditure and energy substrate preference will be determined in mice subjected to MCT-rich diet via indirect calorimetry measurements. Aims: This research proposal will encompass 2 specific aims; (1) To determine whether the ketogenic enzyme (HMGCS2) is augmented in the liver following treatment with MCT, and (2) to assess whether MCT treatment increases hepatic mitochondrial function. In aim 1, we will treat cultured HepG2 with different forms and concentrations of MCT, and assess mRNA/protein expression profile of ketogenic metabolic pathway. Furthermore, we will measure circulating KB in mice subjected to MCT-rich diet and assess their whole body O2 consumption rates and respiratory exchange ratio via indirect calorimetry. In aim 2, we will assess a number of key factors involved in mitochondrial function. Impact: Our findings will yield insight into the mechanism by which MCT supplement enhances ketone body production rates and hepatic mitochondrial function. Moreover, the results of this research program also provide significant insights into what “claims” should be allowed for manufacturers who market MCT as an over-the-counter nutraceutical dietary supplement to augment KB.