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

Abstract

Although lipid-derived acetyl-coenzyme A (CoA) is a major carbon source for histone acetylation, the contribution of fatty acid β-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 sequencing identified diminished interferon-stimulated gene expression in the absence of ACAT1. Chromatin accessibility at the <i>Stat1</i> locus was diminished in ACAT1^-/- cells. Chromatin immunoprecipitation analysis demonstrated reduced acetyl-H3 binding to <i>Stat1</i> promoter/enhancer regions, and increasing histone acetylation rescued <i>Stat1</i> expression. Interferon-β release was blunted in ACAT1^-/- and recovered by ACAT1 reconstitution. Furthermore, ACAT1-dependent histone acetylation required an intact acetylcarnitine shuttle. Last, obese subjects' monocytes exhibited increased ACAT1 and histone acetylation levels. Thus, our study identifies an intriguing link between FAO-mediated epigenetic control of type I interferon signaling and uncovers a potential mechanistic nexus between obesity and type I interferon signaling.