Nutrient sensing (i.e. the ability of cells and organisms to sense, report on, and respond to nutrient availability) is a fundamental mechanism that is essential to life and health, but often dysregulated in the context of diseases. While the discovery of sensing mechanisms for some nutrients, such as amino acids and ATP, have yielded critical insight into their implications for disease, the mechanisms other essential metabolites may be sensed remains unexplored. Acetyl-CoA is a metabolite at the intersection of several catabolic, anabolic, and signaling pathways, and therefore, may be uniquely positioned to report on nutrient availability. Indeed, data from our lab and others indicates that acetyl-CoA availability is sensed. Specifically, our lab has previously shown that upon deletion or inhibition of ATP-citrate lyase (ACLY), cells and tissues upregulate Acetyl-CoA synthetase short chain family member 2 (ACSS2) in order to maintain nuclear-cytosolic pools of acetyl-CoA. However, we have a very limited understanding of the mechanisms by which cells sense acetyl-CoA and how this sensing pathway can subsequently engage adaptive responses when acetyl-CoA production via ACLY is compromised. Notably, a liver-specific inhibitor against ACLY is currently in phase 3 clinical trials for the treatment of hypercholesterolemia. Despite this clinical therapeutic and the potential for the inhibitor to be widely used in individuals with metabolic diseases, studies with genetic models of hepatic ACLY deficiency are lacking, and in particular, no studies have investigated the implications of ACLY loss and subsequent compensatory ACSS2 upregulation in metabolic liver disease, such as non-alcoholic fatty liver disease (NAFLD). Based on my preliminary data, I hypothesize i) that the sensitivity of the mevalonate and cholesterol pathway to ACLY loss mediates ACSS2 upregulation via activation of SREBP transcription factors and ii) that suppression of lipogenic acetyl-CoA production and activation of this sensing mechanism has implications in the pathogenesis of NAFLD by causing a defect in mitochondrial function and fatty acid oxidation. I will test this hypothesis, first (aim 1) through quantification of cholesterol pathway metabolites and assessment of SREBP transcriptional activity, using both an in vitro and in vivo model of ACLY deficiency. Further, I will characterize (aim 2) the effect of suppressing lipogenic acetyl-CoA production an in vivo model of hepatic steatosis. Specifically, I will investigate how a deficit in lipogenic acetyl-CoA production alters fatty acid oxidation and mitochondrial function, and determine whether these changes are dependent on alterations in levels of the mevalonate pathway product, ubiquinone. Overall, I expect the results of this study to address an essential mechanism in acetyl-CoA sensing, as well as the functional consequences of targeting acetyl-CoA metabolism in NAFLD, with the potential to impact treatment strategies of existing therapeutics.
Metabolic diseases represent a rising public health burden in the US, and are frequently characterized by a deficiency in the ability of tissues to correctly gauge the availability of nutrients, leading to their improper storage and utilization. Acetyl-CoA is an essential cellular metabolite that can be made from the breakdown of carbohydrates, fats, and proteins, and despite the presence of inhibitors against acetyl-CoA metabolism in clinical trials, the way in which cells detect acetyl-CoA availability is poorly understood. The work described here will improve our fundamental understanding of how acetyl-CoA is sensed by cells and how alterations in these mechanisms might contribute to non-alcoholic fatty liver disease, a condition affecting approximately one-third of individuals in the US.
