Basal Autophagy Is Necessary for A Pharmacologic PPARα Transactivation

Abstract

Autophagy is a conserved cellular process of catabolism leading to nutrient recycling upon starvation and maintaining tissue and energy homeostasis. Tissue-specific loss of core-autophagy-related genes often triggers diverse diseases, including cancer, neurodegeneration, inflammatory disease, metabolic disorder, and muscle disease. The nutrient-sensing nuclear receptors peroxisome proliferator-activated receptor α (PPARα) plays a key role in fasting-associated metabolisms such as autophagy, fatty acid oxidation, and ketogenesis. Here we show that autophagy defects impede the transactivation of PPARα. Liver-specific ablation of the Atg7 gene in mice showed reduced expression levels of PPARα target genes in response to its synthetic agonist ligands. Since NRF2, an antioxidant transcription factor, is activated in autophagy-deficient mice due to p62/SQSTM1 accumulation and its subsequent interaction with KEAP1, an E3 ubiquitin ligase. We hypothesize that the nuclear accumulation of NRF2 by autophagy defects blunts the transactivation of PPARα. Consistent with this idea, we find that NRF2 activation is sufficient to inhibit the pharmacologic transactivation of PPARα, which is dependent on the Nrf2 gene. These results reveal an unrecognized requirement of basal autophagy for the transactivation of PPARα by preventing NRF2 from a nuclear translocation and suggest a clinical significance of basal autophagy to expect a pharmacologic efficacy of synthetic PPARα ligands.