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

TY - JOUR

T1 - Lipids Reprogram Metabolism to Become a Major Carbon Source for Histone Acetylation

AU - McDonnell, Eoin

AU - Crown, Scott B

AU - Fox, Douglas B

AU - Kitir, Betül

AU - Ilkayeva, Olga R

AU - Olsen, Christian A

AU - Grimsrud, Paul A

AU - Hirschey, Matthew D

N1 - Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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.

AB - 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.

U2 - 10.1016/j.celrep.2016.10.012

DO - 10.1016/j.celrep.2016.10.012

M3 - Journal article

C2 - 27806287

SN - 2211-1247

VL - 17

SP - 1463

EP - 1472

JO - Cell Reports

JF - Cell Reports

IS - 6

ER -