ACC enzymes and protein acetylation

描述（由申请人提供）：脂肪肝疾病影响超过20%的美国人；然而，目前还没有有效的治疗方案。乙酰辅酶a羧化酶（ACC） 1和ACC2促进肝脏脂肪合成；因此，它们是治疗脂肪肝和相关疾病的有吸引力的药物靶点。为了确定肝脏中ACC活性的丧失如何影响肝脏和全身代谢，我们产生了肝脏特异性ACC1和ACC2双敲除小鼠（LDKO）。我们发现这些小鼠免受饮食诱导的葡萄糖耐受不良的影响，但肝脏脂肪的积累出乎意料地增加。我们的初步数据表明，当ACC酶被抑制时，它们的底物乙酰辅酶a被用于蛋白质乙酰化。在这项研究中，我们将测试长期ACC抑制对脂肪肝病理的影响，并确定是否维持ACC1或ACC2的一些残留ACC活性可以通过防止蛋白质超乙酰化来解除对葡萄糖耐量增加的积极影响。这项工作将促进我们对ACC酶对肝脏代谢的分子调控的理解。此外，本研究将指导未来在开发肝脏靶向的同型保留ACC抑制剂治疗脂肪肝和相关代谢紊乱方面的药理学研究。

DESCRIPTION (provided by applicant): Fatty liver disorders affect more than 20% of Americans; however, there are no effective treatment options. The enzymes acetyl-CoA carboxylase (ACC) 1 and ACC2 promote fat synthesis in the liver; therefore, they are attractive drug targets for fatty liver disease and related disorders. To determine how the loss of ACC activity in the liver affects hepatic and whole body metabolism, we generated liver-specific ACC1 and ACC2 double knockout mice (LDKO). We find that these mice are protected from diet-induced glucose intolerance, but accumulate an unexpected increase in liver fat. Our preliminary data suggest that when ACC enzymes are inhibited their substrate acetyl-CoA is used for protein acetylation. In this study we will test the consequences of long-term ACC inhibition on fatty liver disease pathologies and we will determine whether maintaining some residual ACC activity at ACC1 or ACC2 may uncouple the positive effects on glucose tolerance from the increased fat accumulation by preventing protein hyper-acetylation. This work will advance our understanding of the molecular regulation of liver metabolism by ACC enzymes. In addition, this study will guide future pharmacology in the area of developing liver-targeted isotype-sparing ACC inhibitors for the treatment fatty liver disease and related metabolic disorders.