Lipids Reprogram Metabolism to Become a Major Carbon Source for Histone Acetylation.
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. Using13C-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.
Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, 300 N Duke Street, Durham, NC 27701, USA; Department of Medicine, Duke University, Durham, NC 27710, USA.
Eoin
E
McDonnell
Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, 300 N Duke Street, Durham, NC 27701, USA.
Scott B
SB
Crown
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Douglas B
DB
Fox
Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Betül
B
Kitir
Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, 300 N Duke Street, Durham, NC 27701, USA.
Olga R
OR
Ilkayeva
Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Christian A
CA
Olsen
Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, 300 N Duke Street, Durham, NC 27701, USA.
Paul A
PA
Grimsrud
Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, 300 N Duke Street, Durham, NC 27701, USA; Department of Medicine, Duke University, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. Electronic address: matthew.hirschey@duke.edu.
Matthew D
MD
Hirschey
D000105:Acetyl Coenzyme A / Q000378:metabolism; D000107:Acetylation / Q000187:drug effects; D000595:Amino Acid Sequence; D000818:Animals; D002210:Caprylates / Q000494:pharmacology*; D002244:Carbon / Q000494:pharmacology*; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D010084:Oxidation-Reduction
D002210:Caprylates; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D000105:Acetyl Coenzyme A; D002244:Carbon
acetylation; epigenetics; fatty acid; gene expression; histone; lipids; metabolism; metabolomics; proteomics