ACC enzymes and protein acetylation

描述(申请人提供)：脂肪肝疾病影响超过20%的美国人；然而，没有有效的治疗选择。乙酰辅酶A羧基酶(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的ACC1和ACC2双基因敲除小鼠(LDKO)。我们发现，这些小鼠可以免受饮食诱导的葡萄糖耐量异常的影响，但肝脏脂肪却意外增加。我们的初步数据表明，当ACC酶被抑制时，其底物乙酰-辅酶A被用于蛋白质的乙酰化。在这项研究中，我们将测试长期抑制ACC对脂肪肝疾病病理的影响，并确定在ACC1或ACC2保持一些残留的ACC活性是否可以通过防止蛋白质超乙酰化而使糖耐量增加的积极作用与脂肪积累的增加脱钩。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，这项研究将指导未来在开发肝靶向同型节约型ACC抑制剂用于治疗脂肪肝疾病和相关代谢紊乱方面的药理学。

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.