HNF4 Regulates β-Oxidation and is Indispensable for Intestinal Stem Cell Renewal

Intestinal stem cell (ISC) function is regulated by diet and cellular metabolism; however, regulatory mechanisms controlling ISC metabolism are not fully understood. HNF4 transcription factors are important regulators of metabolism, but their functions in ISCs are not elucidated. Here, we demonstrate that fatty acid oxidation (FAO) supports ISC renewal, and HNF4 transcription factors bind to and activate the FAO gene program. Loss of HNF4 paralogs reduces fatty acid oxidation and instead increases fatty acid synthesis. Compound mutant mice reveal that HNF4 transcription factors function redundantly to promote ISC renewal. HNF4 loss leads to reduced levels of FAO gene transcripts, FAO activity and TCA metabolites. Metabolic intervention partially restores TCA metabolites and ISC function in the absence of HNF4. These findings link core cellular transcription factor networks with metabolic state to broaden our understanding of metabolic regulation in stem cell homeostasis.