PT  - JOURNAL ARTICLE
AU  - Kyle S. Cavagnini
AU  - Michael J. Wolfgang
TI  - Pparα and fatty acid oxidation coordinate hepatic transcriptional architecture
AID  - 10.1101/2021.07.12.451949
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.07.12.451949
4099  - http://biorxiv.org/content/early/2021/07/18/2021.07.12.451949.short
4100  - http://biorxiv.org/content/early/2021/07/18/2021.07.12.451949.full
AB  - Fasting requires tight coordination between the metabolism and transcriptional output of hepatocytes to maintain systemic glucose and lipid homeostasis. Genetically-defined deficits in hepatic fatty acid oxidation result in dramatic fasting-induced hepatocyte lipid accumulation and induction of genes for oxidative metabolism, thereby providing a mouse model to interrogate the mechanisms by which the liver senses and transcriptionally responds to fluctuations in lipid levels. While fatty acid oxidation is required for a rise in acetyl-CoA and subsequent lysine acetylation following a fast, changes in histone acetylation (total, H3K9ac, and H3K27ac) associated with transcription do not require fatty acid oxidation. Instead, excess fatty acids prompt induction of lipid catabolic genes largely via ligand-activated Pparα. We observe that active enhancers in fasting mice are enriched for Pparα binding motifs, and that inhibition of hepatic fatty acid oxidation results in elevated enhancer priming and acetylation proximal to Pparα binding sites within regulatory elements largely associated with genes in lipid metabolism. Also, a greater number of Pparα-associated H3K27ac signal changes occur at active enhancers compared to promoters, suggesting a genomic mechanism for Pparα to tune target gene expression levels. Overall, these data demonstrate the requirement for Pparα activation in maintaining transcriptionally permissive hepatic genomic architecture particularly when fatty acid oxidation is limiting.HIGHLIGHTSFasting-induced transcription and histone acetylation are largely independent of acetyl-CoA concentration.Deficits in fatty acid oxidation prompt epigenetic changes and Pparα-sensitive transcription.Fasting prompts enhancer priming and acetylation proximal to Pparα binding sites independent of Pparα.Patterns of Pparα target genes can be distinguished by epigenetic marks at promoters and enhancers.Competing Interest StatementThe authors have declared no competing interest.