The Mitochondrial Calcium Uniporter: Implications for NAFLD and Hepatic Insulin Resistance

项目摘要/摘要 据预测，到2050年，2型糖尿病(T2D)将影响三分之一的美国人，但这一比例很低 可用于治疗胰岛素抵抗的根本原因的治疗方法：异位脂肪堆积。不足 线粒体氧化在T2D和非酒精性脂肪性肝病(NAFLD)的发病机制中起重要作用； 然而，人们对这背后的机制知之甚少。Key TCA的钙依赖特性 酶(丙酮酸脱氢酶、α-酮戊二酸脱氢酶和异柠檬酸脱氢酶)与 线粒体钙作为线粒体新陈代谢的主要调节器。此外，钙最近被 被认为是胰高血糖素诱导的肝脏线粒体氧化改变的关键介质。最近的 线粒体钙单转运体(MCU)的发现重新引起了人们对线粒体的兴趣 钙信号，但MCU在介导肥胖相关代谢功能障碍中的作用尚未得到证实 调查过了。确定线粒体钙调节肝脏生理和功能的机制 代谢对了解NAFLD和肝脏胰岛素抵抗的发病机制至关重要，并具有 将MCU确定为新的药物靶点的可能性。 这项工作将有助于阐明肝脏MCU调节线粒体代谢的机制。 以及这如何导致非酒精性脂肪肝和肝脏胰岛素抵抗。中心假设是MCU扮演着一个 调节肝内脂肪分解和胰高血糖素诱导的肝脏改变在能量平衡中的关键作用 葡萄糖的产生和线粒体的氧化。这将使用一种新的位置同位素核磁共振来解决 直接评估体内线粒体通量速率的示踪分析方法。 综上所述，这项工作将确定MCU在肝脏胰高血糖素信号转导和肥胖相关疾病中的作用 线粒体功能障碍。

Project Summary/Abstract Type 2 diabetes (T2D) is predicted to impact one third of Americans by the year 2050, yet there are few treatments available to treat the root cause of insulin resistance: ectopic lipid accumulation. Insufficient mitochondrial oxidation plays a role in the pathogenesis of T2D and non-alcoholic fatty liver disease (NAFLD); however, the mechanisms behind this are poorly understood. The calcium-dependent nature of key TCA enzymes (pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and isocitrate dehydrogenase) implicate mitochondrial calcium as a master regulator of mitochondrial metabolism. Additionally, calcium has recently been implicated as a critical mediator of glucagon-induced alterations in hepatic mitochondrial oxidation. The recent identification of the mitochondrial calcium uniporter (MCU) has sparked a renewed interest in mitochondrial calcium signaling, yet a role for MCU in mediating obesity-associated metabolic dysfunction has not been investigated. Determining the mechanism by which mitochondrial calcium regulates liver physiology and metabolism is critical to understanding the pathogenesis of NAFLD and hepatic insulin resistance, and has the potential to identify MCU as a novel drug target. This work will serve to elucidate the mechanisms by which hepatic MCU regulates mitochondrial metabolism, and how this contributes to NAFLD and hepatic insulin resistance. The central hypothesis is that MCU plays a critical role in energy balance by modulating intrahepatic lipolysis and glucagon-induced alterations in hepatic glucose production and mitochondrial oxidation. This will be addressed using a novel positional isotope NMR tracer analysis method to directly assess in vivo rates of mitochondrial fluxes. Taken together, this work will establish the role of MCU in hepatic glucagon signaling and the obesity-associated mitochondrial dysfunction.