Antagonism of the Actions of Peroxisome Proliferator-activated Receptor-α by Bile Acids
The peroxisome proliferator-activated receptor-α (PPARα) is a ligand-activated transcription factor that regulates the expression of a number of genes critical for fatty acid β-oxidation. Because a number of substrates and intermediates of this metabolic pathway serve as ligand activators of this receptor, homeostatic control of fatty acid metabolism is achieved. Evidence also exists for PPARα-dependent regulation of genes encoding critical enzymes of bile acid biosynthesis. To determine whether the primary products of bile acid biosynthesis, cholic acid and chenodeoxycholic acid, were capable of modulating PPARα function, a variety ofin vivoandin vitroapproaches were utilized. Feeding a bile acid-enriched diet significantly reduced the degree of hepatomegaly and induction of target genes encoding enzymes of fatty acid β-oxidation caused by treatment with the potent PPARα ligand Wyeth-14,643. Convergent data from mechanistic studies indicate that bile acids interfere with transactivation by PPARα at least in part by impairing the recruitment of transcriptional coactivators. The results of this study provide the first evidence in favor of the existence of compounds, normally found within the body, that are capable of antagonizing the physiological actions of PPARα. The impact of PPARα antagonism by endogenous bile acids is likely to be limited under normal conditions and to have only minimal effects on bile acid homeostasis. However, during certain pathophysiological states where intracellular bile acid concentrations are elevated, meaningful effects on PPARα-dependent target gene regulation are possible.