Role of ATGL in hepatic energy metabolism

描述（由申请人提供）：非酒精性脂肪性肝病（NAFLD），由三酰甘油（TAG）积累定义，是一种普遍的疾病，涉及许多代谢性疾病的病因，包括肥胖、糖尿病和心血管疾病。尽管TAG代谢的重要性和我们对TAG合成途径的理解取得了进展，但调节肝脏TAG水解的机制及其对疾病病因的影响尚不清楚。本应用程序的目的是确定脂肪TAG脂肪酶（ATGL）在肝脏脂质代谢和信号传导、胰岛素抵抗的病因学和介导饮食特异性作用中的作用。提出的研究假设是ATGL是一种突出的肝脏脂肪酶，通过改变FA通道和信号传导对能量代谢产生广泛的影响。我们的假设基于我们实验室的初步研究，这些研究表明ATGL改变了水解FA在合成代谢和分解代谢途径之间的分配，调节PPAR-1活性，解除NAFLD的胰岛素抵抗，并选择性地水解TAG。这项研究的基本原理是，确定ATGL在介导肝脏TAG代谢中的作用，将为NAFLD的病因和相关合并症提供重要的见解，从而促进营养或药物治疗的发展。该假设将通过三个具体目标进行验证：1)表征ATGL和PPAR-1信号轴及其在肝脏能量代谢中的作用；2)确定肝脏ATGL在调节肝脏和全身胰岛素抵抗中的作用；3)表征肝脏ATGL在水解不同TAG池和介导后续FA通道和信号传导中的作用。在第一个目标下，在小鼠模型中进行ATGL获得或丧失功能的研究将确定ATGL与PPAR-a之间的关系。此外，体外研究将确定ATGL调节PPAR-1活性的机制。第二个目标将采用体外和体内方法以及稳定同位素技术来表征ATGL如何从胰岛素抵抗中解耦肝脏TAG积累及其在脂质信号分子形成中的作用。第三个目标将定义肝脏ATGL如何调节来自不同底物的TAG-FA的信号传导和通道，并介导饮食对代谢的特异性影响。这些研究具有创新性，因为它们从TAG水解的研究不足和经常被忽视的途径来研究NAFLD及其合并症。了解肝脏TAG水解是如何被调节的是很重要的，因为它不仅影响TAG的积累，而且还决定了水解FA的代谢命运和信号特性，最终可以影响许多生物过程。

DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disease (NAFLD), defined by triacylglycerol (TAG) accumulation, is a prevalent disorder that is involved in the etiology of numerous metabolic diseases including obesity, diabetes and cardiovascular disease. Despite the importance of TAG metabolism and the advancements into our understanding of the TAG synthetic pathway, the mechanisms regulating hepatic TAG hydrolysis and their effects on disease etiology are unknown. The objective of this application is to define the role of adipose TAG lipase (ATGL) in hepatic lipid metabolism and signaling, the etiology of insulin resistance and in mediating diet-specific effects. The hypothesis of the proposed studies is that ATGL is a prominent hepatic lipase that elicits wide-ranging effects on energy metabolism by altering FA channeling and signaling. We base this hypothesis on Preliminary Studies from our laboratory showing that ATGL alters partitioning of hydrolyzed FA between anabolic and catabolic pathways, regulates PPAR-1 activity, uncouples insulin resistance from NAFLD and selectively hydrolyzes TAG. The rationale for the proposed research is that identifying the role of ATGL in mediating hepatic TAG metabolism will provide significant insight into the etiology of NAFLD and related comorbidities, thereby, advancing the possibilities for development of nutritional or pharmaceutical therapies. The hypothesis will be tested using three specific aims: 1) to characterize the ATGL and PPAR-1 signaling axis and its role in hepatic energy metabolism, 2) to define the role of hepatic ATGL in regulating hepatic and whole-body insulin resistance and 3) to characterize the effect of hepatic ATGL on hydrolyzing distinct TAG pools and mediating subsequent FA channeling and signaling. Under the first aim, ATGL gain or loss-of-function studies in mouse models will define the relationship between ATGL and PPAR-a. Additionally, in vitro studies will define the mechanisms through which ATGL regulates PPAR-1 activity. The second aim will employ both in vitro and in vivo methodologies along with stable isotope techniques to characterize how ATGL uncouples hepatic TAG accumulation from insulin resistance and its role in the formation of lipid signaling molecules. The third aim will define how hepatic ATGL regulates the signaling and channeling of TAG-FA derived from different substrates and mediates diet-specific effects on metabolism. These studies are innovative because they approach NAFLD and its comorbidities from the understudied and often ignored pathway of TAG hydrolysis. Understanding how hepatic TAG hydrolysis is regulated is significant because it not only impacts TAG accumulation, but also dictates the metabolic fate and signaling properties of the hydrolyzed FA that can ultimately influence a multitude of biological processes.