Lipids Reprogram Metabolism to Become a Major Carbon Source for Histone Acetylation

Highlights

• Fatty acid oxidation increases global histone acetylation

• Lipids can provide up to 90% of acetyl-carbon for histone acetylation

• Octanoate reprograms metabolism and becomes the major source of acetyl-CoA

• Lipid-derived acetyl-CoA promotes lipid-specific gene expression

Summary

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.