Medium Chain Triglycerides and Ketogenesis

中链甘油三酯和生酮

• 批准号: RGPIN-2020-05207
• 负责人: AlBatran, Rami
• 金额: $ 1.75万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=716320
• 关键词: Medium; Chain; Triglycerides; Ketogenesis

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.

背景：中链脂肪酸以中链甘油三酯 (MCT) 形式天然存在，存在于椰子油和棕榈油中。 MCT 有不同的形式，可以作为膳食补充剂（MCT 油）在柜台购买。与其他脂肪酸不同，MCT 可以立即提供能量，因为它们能够非常快速地穿过线粒体双膜，从而产生酮体 (KB)。有趣的是，许多研究表明 MCT 补充剂可提高循环 KB 并提高运动表现。然而，MCT 的生物学作用以及 MCT 增强酮体产生（生酮）的机制尚未得到充分研究。因此，该提案的主要目的是阐明 MCT 补充剂增加肝脏生酮作用的机制，从而增强肝脏线粒体功能。 假设：我们假设 MCT 补充剂通过增强生酮酶线粒体 3-羟甲基戊二酰辅酶 A 合酶 (HMGCS2) 来增加循环 KB，从而改善肝线粒体功能。 方法：我们将利用多种细胞培养和动物方法来揭示 MCT 补充剂如何提高肝脏中 KB 的生产率。这包括用不同形式和浓度的 MCT 培养和处理肝细胞系 (HepG2)，以及评估生酮酶和肝线粒体功能。此外，我们将让小鼠接受富含 MCT 的饮食 12 周，通过肝脏提取物的 mRNA/蛋白表达谱来确定 MCT 治疗是否会增加循环 KB、增强生酮途径（例如 HMGCS2）和肝线粒体功能。此外，将通过间接量热法测量来确定富含 MCT 饮食的小鼠的能量消耗和能量底物偏好。 目标：本研究提案将包含 2 个具体目标； (1) 确定 MCT 治疗后肝脏中的生酮酶 (HMGCS2) 是否增强，以及 (2) 评估 MCT 治疗是否会增加肝线粒体功能。在目标1中，我们将用不同形式和浓度的MCT处理培养的HepG2，并评估生酮代谢途径的mRNA/蛋白质表达谱。此外，我们将测量富含 MCT 饮食的小鼠的循环 KB，并通过间接量热法评估其全身 O2 消耗率和呼吸交换率。在目标 2 中，我们将评估涉及线粒体功能的一些关键因素。 影响：我们的研究结果将深入了解 MCT 补充剂增强酮体生成率和肝线粒体功能的机制。此外，该研究项目的结果还为将 MCT 作为非处方营养膳食补充剂销售以增强 KB 的制造商应允许哪些“声明”提供了重要见解。