Nutrient-Sensing Nuclear Receptor <i>PPARα</i> Controls Liver Proteostasis

Abstract Peroxisome proliferator-activated receptor alpha ( PPARα ) is a nuclear receptor that orchestrates metabolic adaptation to fasting by regulating hepatic lipid and glucose metabolism. While these functions are well established, its role in protein homeostasis, another energy-intensive process, has remained unclear. Here, we performed multi-omics analyses in wild-type and PPARα knockout mice treated with the PPARα agonist fenofibrate to define its broader role in proteostasis. Interestingly, chronic PPARα activation suppressed hepatic secretory pathways, reducing secretome gene expression and circulating serum proteins, and downregulated genes involved in endoplasmic reticulum (ER) translocation, glycosylation, folding, and trafficking. Concurrently, PPARα activation enhanced proteasome activity, which was associated with selective induction of proteasome 26S subunit non-ATPase (PSMD) family members. In addition, hepatic protein synthesis was strongly attenuated. This was associated with an increase in the inhibitory phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α), that in turn was linked to disrupted iron homeostasis. Together, these findings identify PPARα as a regulator of proteostasis, suppressing protein synthesis and secretion while promoting protein degradation pathways. Beyond its canonical role in lipid and glucose metabolism, we conclude that PPARα exerts an additional energy-conserving function by coordinating proteostasis, expanding our understanding of its systemic metabolic role.