FATTY ACYL-COA THIOESTERS ARE LIGANDS OF HEPATIC NUCLEAR FACTOR-4-ALPHA

Dietary fatty acids specifically modulate the onset and progression of various diseases, including cancer(1,2), atherogenesis(3), hyperlipid aemia(4), insulin resistance(5) and hypertension(6), as well as blood coagulability and fibrinolytic defects(7); their effects depend on the ir chain length and degree of saturation. Hepatocyte nuclear factor-4 alpha (ref. 8) (HNF-4 alpha) is an orphan transcription factor of the superfamily of nuclear receptors and controls the expression of genes (reviewed in ref. 9) that govern the pathogenesis and course of some o f these diseases. Here we show that long-chain fatty acids directly mo dulate the transcriptional activity of HNF-4 alpha by binding as their acyl-CoA thioesters to the ligand-binding domain of HNF-4 alpha, This binding may shift the oligomeric-dimeric equilibrium of HNF-4 alpha o r may modulate the affinity of HNF-4 alpha for its cognate promoter el ement, resulting in either activation or inhibition of HNF-4 alpha tra nscriptional activity as a function of chain length and the degree of saturation of the fatty acyl-CoA ligands, In addition to their roles a s substrates to yield energy, as an energy store, or as constituents o f membrane phospholipids, dietary fatty acids may affect the course of a disease by modulating the expression of HNF-4 alpha-controlled gene s.