Fatty acyl-CoA thioesters are ligands of hepatic nuclear factor-4α

Rachel Hertz, Judith Magenheim, Inna Berman and Jacob Bar-Tana ()
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Rachel Hertz: Faculty of Medicine, Hebrew University
Judith Magenheim: Faculty of Medicine, Hebrew University
Inna Berman: Faculty of Medicine, Hebrew University
Jacob Bar-Tana: Faculty of Medicine, Hebrew University

Nature, 1998, vol. 392, issue 6675, 512-516

Abstract: Abstract Dietary fatty acids specifically modulate the onset and progression of various diseases, including cancer1,2, atherogenesis3, hyperlipidaemia4, insulin resistance5 and hypertension6, as well as blood coagulability and fibrinolytic defects7; their effects depend on their chain length and degree of saturation. Hepatocyte nuclear factor-4α (ref. 8) (HNF-4α) 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 of these diseases. Here we show that long-chain fatty acids directly modulate the transcriptional activity of HNF-4α by binding as their acyl-CoA thioesters to the ligand-binding domain of HNF-4α. This binding may shift the oligomeric–dimeric equilibrium of HNF-4α or may modulate the affinity of HNF-4α for its cognate promoter element, resulting in either activation or inhibition of HNF-4α transcriptional activity as a function of chain length and the degree of saturation of the fatty acyl-CoA ligands. In addition to their roles as substrates to yield energy, as an energy store, or as constituents of membrane phospholipids, dietary fatty acids may affect the course of a disease by modulating the expression of HNF-4α-controlled genes.

Date: 1998
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DOI: 10.1038/33185

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