Norbert Leitinger, PhD
Norbert Leitinger, PhD, a professor of pharmacology and associate director of UVA’s Robert M. Berne Cardiovascular Research Center, was awarded a $2.5 million grant, for a project to study Acetyl CoA Carboxylase in the metabolic control of inflammation.
The rapid induction of the inflammatory response is essential for the recruitment of immune cells to sites of injury or infection; however, prolonged states of hyperinflammation result in failure to resolve inflammation and restore homeostasis. Metabolic adaptation is central to both the induction and resolution of inflammation, and immune cells such as macrophages must rapidly rewire their cellular metabolism to successfully carry out effector functions. The inflammatory response in cells requires a metabolic switch to aerobic glycolysis with concomitant downregulation of oxidative phosphorylation. For reasons that are incompletely understood, there is also an increase in lipid biosynthesis in response to pathogens, which results in accumulation of excess lipid in macrophages.
Acetyl CoA Carboxylase (ACC) is a central enzyme directly regulating de novo lipogenesis as well as indirectly affecting transcriptional capacity by regulating acetyl-CoA levels, histone acetylation and chromatin accessibility. In his PhD thesis, medical scientist training program student Scott Yeudall identified ACC as a key enzyme regulating the inflammatory response in macrophages [Science Advances, 8(47):eabq1984, 2022, PMID: 36417534], providing an opportunity to investigate the link between lipid metabolism and inflammation in immune cells.
The project will use genetic approaches, bioenergetics analysis, metabolomics and lipidomics to determine the role of ACC isoforms in the inflammation-driven metabolic response and the production of pro-resolving lipid mediators by macrophages and in murine models of bacterial infection. Since ACC inhibitors are being tested in clinical trials in patients with fatty liver disease and certain cancers, it will be important to examine the role of ACC in host response to infections. The proposed research will also identify if separate inhibition of individual ACC isoforms will be beneficial.
Collaborators include James Casanova, PhD, in the Department of Cell Biology and Ku-Lung (Ken) Hsu, PhD, in the Department of Chemistry.
Read more about the Leitinger Laboratory.