Role of ATGL in hepatic energy metabolism

描述(申请人提供)：非酒精性脂肪性肝病(NAFLD)，由三酰甘油(TAG)蓄积定义，是一种普遍存在的疾病，涉及多种代谢性疾病的病因，包括肥胖、糖尿病和心血管疾病。尽管TAG代谢的重要性以及对TAG合成途径的深入了解，但调节肝脏TAG水解的机制及其在疾病病因学中的作用尚不清楚。本应用的目的是确定脂肪标签脂肪酶(ATGL)在肝脏脂质代谢和信号转导中的作用，胰岛素抵抗的病因以及在调节饮食特异性效应中的作用。这些研究的假设是，ATGL是一种重要的肝脂酶，通过改变FA的通道和信号，对能量代谢产生广泛的影响。我们基于我们实验室的初步研究表明，ATGL改变了水解物FA在合成代谢和分解代谢途径之间的分配，调节了PPAR-1的活性，使胰岛素抵抗与NAFLD解偶联，并选择性地水解TAG。这项研究的基本原理是，确定ATGL在调节肝脏TAG代谢中的作用将有助于深入了解NAFLD及其相关并发症的病因学，从而促进营养或药物治疗的发展。这一假说将通过三个特定的目标进行验证：1)确定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在分解不同的Tag池和介导随后的FA通道和信号传递方面的作用。在第一个目标下，在小鼠模型中进行的ATGL获得或功能丧失的研究将确定ATGL和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。第二个目标将使用体外和体内方法以及稳定同位素技术来表征ATGL如何将肝脏标签的积累与胰岛素抵抗分开，以及它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的信号和通道，并调节饮食对新陈代谢的特定影响。这些研究具有创新性，因为它们从未被研究和经常被忽视的TAG水解途径来探讨NAFLD及其共病。了解肝脏TAG水解酶是如何调控的具有重要意义，因为它不仅影响TAG的积累，而且还决定着水解物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.