Mitochondrial fatty acid oxidation regulates monocytic type I interferon signaling via histone acetylation.

Although lipid-derived acetyl-CoA is a major carbon source for histone acetylation, the contribution of fatty acid ?-oxidation (FAO) to this process remains poorly characterized. To investigate this, we generated mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1, distal FAO enzyme) knockout macrophages. 13C-carbon tracing confirmed reduced FA-derived carbon incorporation into histone H3 and RNA-seq identified diminished interferon stimulated gene expression in the absence of ACAT1. Chromatin accessibility at Stat1 locus was diminished in ACAT1-/- cells. CHIP analysis demonstrated reduced acetyl-H3 binding to Stat1 promoter/enhancer regions and increasing histone acetylation rescued Stat1 expression. IFNß release was blunted in ACAT1-/- and recovered by ACAT1 reconstitution. Furthermore, ACAT1-dependent histone acetylation required an intact acetylcarnitine shuttle. Finally, obese subjects' monocytes exhibited increased ACAT1 and histone acetylation levels. Thus, our study identifies a novel link between FAO-mediated epigenetic control of type 1 interferon signaling and uncovers a potential mechanistic link between obesity and type I inferon signaling. Overall design: To investigate role of fatty acid oxidation on immunity, we generated mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) knockout macrophages.