Cells integrate nutrient sensing and metabolism to coordinate cellular growth. 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 show that lipid-derived acetyl-CoA is also a major source of carbon for histone acetylation. Fatty acid oxidation leads to global cellular metabolic reprogramming and represses glucose and glutamine metabolism, thereby increasing intracellular lipid-derived acetyl-CoA. We traced 13C-carbon from lipid onto histones, demonstrating that up to 90% of histone acetylation can be derived from fatty acid carbon. Gene expression profiling of octanoate-treated hepatocytes identified genes involved in lipid metabolic processes are positively correlated. Conversely, cell cycle processes are negatively correlated, consistent with a suppression of proliferation upon lipid treatment. These studies uncover how fatty acid sensing and metabolism are integrated by epigenetic events that control gene expression, together ensuring proper cellular response to metabolites for growth.