Pparα and fatty acid oxidation coordinate hepatic transcriptional architecture

Abstract

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 Ppar. We observe that active enhancers in fasting mice are enriched for Ppar binding motifs, and that inhibition of hepatic fatty acid oxidation results in elevated enhancer priming and acetylation proximal to Ppar binding sites within regulatory elements largely associated with genes in lipid metabolism. Also, a greater number of Ppar-associated H3K27ac signal changes occur at active enhancers compared to promoters, suggesting a genomic mechanism for Ppar to tune target gene expression levels. Overall, these data demonstrate the requirement for Ppar activation in maintaining transcriptionally permissive hepatic genomic architecture particularly when fatty acid oxidation is limiting. HIGHLIGHTSO_LIFasting-induced transcription and histone acetylation are largely independent of acetyl-CoA concentration. C_LIO_LIDeficits in fatty acid oxidation prompt epigenetic changes and Ppar-sensitive transcription. C_LIO_LIFasting prompts enhancer priming and acetylation proximal to Ppar binding sites independent of Ppar. C_LIO_LIPatterns of Ppar target genes can be distinguished by epigenetic marks at promoters and enhancers. C_LI