Lipids Reprogram Metabolism to Become a Major Carbon Source for Histone Acetylation
Eoin McDonnell,
Scott B. Crown,
Douglas B. Fox,
Betül Kitir,
Olga R. Ilkayeva,
Christian A. Olsen,
Paul A. Grimsrud,
Matthew D. Hirschey
Affiliations
Eoin McDonnell
Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, 300 N Duke Street, Durham, NC 27701, USA
Scott B. Crown
Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, 300 N Duke Street, Durham, NC 27701, USA
Douglas B. Fox
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA
Betül Kitir
Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
Olga R. Ilkayeva
Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, 300 N Duke Street, Durham, NC 27701, USA
Christian A. Olsen
Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
Paul A. Grimsrud
Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, 300 N Duke Street, Durham, NC 27701, USA
Matthew D. Hirschey
Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, 300 N Duke Street, Durham, NC 27701, USA
Cells integrate nutrient sensing and metabolism to coordinate proper cellular responses to a particular nutrient source. For example, glucose drives a gene expression program characterized by activating genes involved in its metabolism, in part by increasing glucose-derived histone acetylation. Here, we find that lipid-derived acetyl-CoA is a major source of carbon for histone acetylation. Using 13C-carbon tracing combined with acetyl-proteomics, we show that up to 90% of acetylation on certain histone lysines can be derived from fatty acid carbon, even in the presence of excess glucose. By repressing both glucose and glutamine metabolism, fatty acid oxidation reprograms cellular metabolism, leading to increased lipid-derived acetyl-CoA. Gene expression profiling of octanoate-treated hepatocytes shows a pattern of upregulated lipid metabolic genes, demonstrating a specific transcriptional response to lipid. These studies expand the landscape of nutrient sensing and uncover how lipids and metabolism are integrated by epigenetic events that control gene expression.
