RNF128 regulates the adaptive metabolic response to fasting by modulating PPARα function

Peroxisome proliferator-activated receptor alpha (PPARα) is a crucial transcriptional factor that regulates fatty acid β-oxidation and ketogenesis in response to fasting. However, the mechanisms underlying PPARα function remain unclear. This study identified a novel PPARα-binding protein-RING finger protein 128 (RNF128)-that facilitates PPARα polyubiquitination, resulting in the degradation and suppression of PPARα function during fasting. Furthermore, RNF128 overexpression inhibited fibroblast growth factor 21 expression and lipid metabolism-related genes by facilitating PPARα degradation during fasting. In contrast, silencing RNF128 expression enhanced PPARα-dependent fatty acid β-oxidation and ketogenesis in starved cells. In vivo experiments demonstrated that RNF128 deficiency also significantly reduced lipid levels while increasing fatty acid β-oxidation and ketogenesis during fasting. Adeno-associated virus serotype 8-mediated RNF128 overexpression resulted in increased lipid levels and decreased expression of genes related to fatty acid β-oxidation and ketogenesis in fasted mice. Our findings revealed that RNF128 is crucial for metabolic adaptation to fasting in the liver by interacting with PPARα, thereby enhancing its polyubiquitination and degradation. Therefore, RNF128 is a novel regulator of PPARα function under nutrient-deprived conditions.