PPAR alpha/RXR alpha downregulates amino acid catabolism in the liver via interaction with HNF4 alpha promoting its proteasomal degradation

The preservation of body proteins is essential to guarantee their functions in organisms. Therefore, the utilization of amino acids as energy substrates is regulated by a precise fine-tuned mechanism. Recent evidence suggests that the transcription factors peroxisome proliferator-activated receptor alpha (PPAR alpha) and hepatocyte nuclear factor 4 alpha (HNF4 alpha) are involved in this regulatory mechanism. Thus, the aim of this study was to determine how these transcription factors interact to regulate the expression of amino acid catabolism genes. In vivo studies using PPAR alpha-knockout mice (Ppar alpha-null) fed different amounts of dietary protein showed that in the absence of PPAR alpha, there was a significant increase in HNF4 alpha abundance in the liver, which corresponded with an increase in amino acid catabolizing enzyme (AACE) expression and the generation of increased amounts of postprandial urea. Moreover, this effect was proportional to the increase in dietary protein consumed. Chromatin immunoprecipitation assays showed that HNF4 alpha can bind to the promoter of AACE serine dehydratase (SDS), an effect that was potentiated by dietary protein in the Ppar alpha-null mice. The mechanistic studies revealed that the presence of retinoid X receptor alpha (RXR alpha) is essential to repress HNF4 alpha activity in the presence of PPAR alpha, and this interaction accelerates HNF4 alpha degradation via the proteasome pathway. These results showed that PPAR alpha can down regulate liver amino acid catabolism in the presence of RXR alpha by inhibiting HNF4 alpha activity. (C) 2021 Elsevier Inc. All rights reserved.

Automated summary

The study found that PPARα plays a key role in inhibiting the activity of HNF4α, thereby affecting liver amino acid catabolism. This regulatory process is influenced by the amount of protein intake and is controlled by RXRα.