ACC enzymes and protein acetylation

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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.