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

Abstract

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.

β-catenin-activated hepatocellular carcinomas are addicted to fatty acids

“…Indeed, in β-catenin-activated HCC, FAO efficiently feeds the electron transfer chain, producing ATP with no uncoupling, rendering them independent from glucose for ATP production. Aside from providing an obvious energy source, boosting FAO confers other advantages to tumour cells, and recent research has highlighted the role of FAO in nicotinamide adenine dinucleotide phosphate (NADPH)homeostasis32 33 and epigenetics modifications 34. Indeed, it has been shown that lipid-derived acetyl-CoA is the main substrate for histone acetylation leading to epigenetic alterations 34.…”

“…Aside from providing an obvious energy source, boosting FAO confers other advantages to tumour cells, and recent research has highlighted the role of FAO in nicotinamide adenine dinucleotide phosphate (NADPH)homeostasis32 33 and epigenetics modifications 34. Indeed, it has been shown that lipid-derived acetyl-CoA is the main substrate for histone acetylation leading to epigenetic alterations 34. In addition, FAO has been suggested to be a pathway that allows NADPH homeostasis for tumour cells under conditions of energetic stress, such as during phases of nutrient deprivation 35 36.…”

Fatty acid oxidation by the osteoblast is required for normal bone acquisition in a sex- and diet-dependent manner

“…However, we cannot completely rule out the possibility that epigenetic mechanisms also contribute to impaired osteoblast differentiation due to Cpt2 deficiency. Much like glucose catabolism, intramitochondrial fatty acid metabolism generates acetyl-CoA that can contribute to chromatin acetylation (53). We plan to explore this possibility in future studies.…”

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model

“…Relative changes in protein acetylation and protein abundance were determined by quantitative mass spectrometry as described previously (21). Briefly, mitochondrial proteins were digested with trypsin and the resulting peptides were labeled with 6-plex Tandem Mass Tags (TMT, Thermo Fisher Scientific).…”