Role of Fbxo48-mediated AMPK proteostasis in the pathogenesis and treatment of NAFLD

项目摘要/摘要 在过去的二十年里，美国超重和肥胖的人数急剧增加。使用 这一上升，一些与肥胖相关的代谢性疾病的流行，如2型糖尿病(T2D)和非肥胖 酒精性脂肪性肝病(NAFLD)也同样直线上升。非酒精性脂肪肝包括一系列肝细胞 改变，包括单纯性脂肪变性和脂肪变性伴炎(NASH)，可导致纤维化、肝硬变和 肝细胞癌。肝脏胰岛素抵抗，线粒体代谢变化，炎症信号， 细胞外小泡信号和/或肠道微生物多样性的改变都被认为与发病有关。 NAFLD和NASH。然而，非酒精性脂肪肝的发病机制尚不完全清楚。 目前还没有批准的治疗NAFLD的方法。5‘-AMP激活的蛋白激酶(AMPK)是一种细胞能量 一种协调代谢途径以平衡能源需求和生产的传感器，越来越多的证据表明 AMPK活性及其下游信号通路的丧失导致了NAFLD的发生。这项提案将考验 假设AMPK依赖的磷酸化、泛素/蛋白酶体介导的降解增加有助于 与肥胖相关的NAFLD的发病机制有关。他们将进一步确定F-box蛋白的身份 介导Skp-Cullin1-Rbx1 E3连接酶复合体对磷酸化AMPK的特异性识别。最后，研究 在此，我们将解决如何调节可能的F-box蛋白的表达或活性在致病过程中。 非酒精性脂肪肝或在确诊的NASH发展后会影响与这些疾病相关的主要结局。这些目标 将通过结合细胞生物学、氨基酸和多肽化学、动物等方法来实现 生理学、代谢同位素示踪和同源建模-基于分子对接的药物设计和 优化。这种方法将利用参与调查的人员的独特和免费的专业知识 多位主要研究人员的建议，导致对发病机制和潜在的治疗方法的新认识 NAFLD。

Project summary/Abstract The number of overweight and obese individuals in the U.S. has increased dramatically over the last two decades. With this rise, the prevalence of a number of obesity-associated metabolic diseases, such as type 2 diabetes (T2D) and non- alcoholic fatty liver disease (NAFLD), has similarly sky rocketed. NAFLD encompasses a range of hepatocellular alterations, including simple steatosis and steatosis with inflammation (NASH), which can lead to fibrosis, cirrhosis and hepatocellular carcinoma. Hepatic insulin resistance, changes in mitochondrial metabolism, inflammatory signaling, extracellular vesicle signaling and/or altered intestinal microbial diversity are all proposed to contribute the pathogenesis of NAFLD and NASH. However, the mechanistic basis for the pathogenesis of NAFLD remains incompletely understood and there are currently no approved treatments for NAFLD. 5'-AMP-activated protein kinase (AMPK) is a cellular energy sensor that coordinates metabolic pathways to balance energy demand with production, and growing evidence suggests that loss of AMPK activity and its downstream signaling pathways contributes to NAFLD. This proposal will test the hypothesis that increased phosphorylation-dependent, ubiquitin/proteasomal-mediated degradation of AMPK contributes to the pathogenesis of obesity-associated NAFLD. They will further establish the identity of the F-box protein that mediates the specific recognition of phosphorylated AMPK by the Skp-Cullin1-Rbx1 E3 ligase complex. Finally, studies herein will address how modulating the expression or activity of the putative F-box protein during the pathogenesis of NAFLD or after development of established NASH impacts major outcomes associated with these diseases. These goals will be achieved through a combination of approaches including cell biology, amino acid and peptide chemistry, animal physiology, metabolic isotope tracing, and homology modeling- and molecular docking-based drug design and optimization. This approach will leverage the unique and complimentary expertise of the participating investigators of this multi-principal investigator proposal, leading to new knowledge regarding the pathogenesis and a potential treatment of NAFLD.