The nuclear receptors PPARα (encoded by NR1C1) and farnesoid X receptor (FXR, encoded by NR1H4) are activated in the liver in the fasted and fed state, respectively. PPARα activation induces fatty acid oxidation, while FXR controls bile acid homeostasis, but both nuclear receptors also regulate numerous other metabolic pathways relevant to liver energy balance. Here we review evidence that they function coordinately to control key nutrient pathways, including fatty acid oxidation and gluconeogenesis in the fasted state and lipogenesis and glycolysis in the fed state. We have also recently reported that these receptors have mutually antagonistic impacts on autophagy, which is induced by PPARα but suppressed by FXR. Secretion of multiple blood proteins is a major drain on liver energy and nutrient resources, and we present preliminary evidence that the liver secretome may be directly suppressed by PPARα, but induced by FXR. Finally, previous studies demonstrated a striking deficiency in bile acid levels in malnourished mice that is consistent with results in malnourished children. We present evidence that hepatic targets of PPARα and FXR are dysregulated in chronic undernutrition. We conclude that PPARα and FXR function coordinately to integrate liver energy balance.
(A) A list of 333 liver-specific genes from Pattern Gene Database (PaGenBase; http://bioinf.xmu.edu.cn/PaGenBase) was compared with an NCBI Gene Expression Omnibus fenofibrate-treated liver microarray (GEO GSE67796). The expression of 145 liver genes was found to be altered (P < 0.01), 110 (75.8%) of which were significantly downregulated by PPARα agonist treatment (hypergeometric test P = 1.89 × 10–38). (B) The 110 common genes were subjected to analysis using Database for Annotation, Visualization and Integrated Discovery (DAVID; https://david.ncifcrf.gov/), to address their cellular compartment (gene ontology–cellular compartment [GO-CC]), biological pathways (gene ontology–biological pathways [GO-BP]), and KEGG pathway associations. A majority of the genes encode secreted proteins located in extracellular space.