Acetyl-CoA metabolism and the regulation of hepatic lipid homeostasis in MASLD

About This Grant

PROJECT SUMMARY Metabolic diseases including metabolic dysfunction-associated steatotic liver disease (MASLD) pose a major threat to economic and healthcare systems worldwide. Accordingly, there is a great need for new therapeutic targets and strategies. Abnormal lipid metabolism in the liver is a hallmark of metabolic disease, and the enzyme ATP-citrate lyase (ACLY), which generates acetyl-CoA for lipid and cholesterol synthesis, has emerged as a promising therapeutic target against liver steatosis. To this point, several ACLY inhibitors have been developed and tested in preclinical studies, and one that specifically targets hepatic ACLY, bempedoic acid, has been FDA approved to treat high cholesterol. Despite this progress, it is now appreciated that there are multiple enzymatic routes to generate lipogenic acetyl-CoA that can be leveraged in different contexts. Our published studies and preliminary data across cell lines and mouse models suggest these pathways have specialized functions, including the production of bioactive lipids important for PPARα signaling. Furthermore, emerging evidence indicates that ACLY also contributes to lipid metabolism in the liver via regulation of gene expression to impact fatty acid oxidation. The diverse mechanisms through which ACLY and BPA influence lipid homeostasis in the liver remain poorly understood; yet they are key to effectively deploying acetyl-CoA metabolism inhibitors to combat MASLD. In this proposal, we will investigate the role of ACLY in mediating diet-dependent lipid metabolism, applying spatio-temporal lipidomics, flux analysis, and gene expression analysis to explore how ACLY regulates PPARα- dependent gene expression (Aim 1). We will also examine ACLY-independent functions of bempedoic acid to elucidate how this drug reshapes metabolism and circadian PPARα signaling (Aim 2). We will leverage genetic mouse models, in vivo stable isotope tracing, lipidomics, mass spectrometry-imaging, and compartmentalized ACLY expression to dissect these pathways. The long-term impact of this work will be a substantially strengthened understanding of the mechanisms through which acetyl-CoA is produced and used in the liver to regulate lipid metabolism, toward the goal of developing improved strategies to treat MASLD.