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

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.

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Figure 1: Long-chain fatty acyl-CoAs are ligands for HNF-4α.
Figure 2: Modulation of HNF-4α activity by long-chain fatty acids in transient transfection.
Figure 3: Modulation of HNF-4α transcriptional activity by long-chain fatty acyl-CoAs in vitro.
Figure 4: Fatty acyl-CoA ligands of HNF-4α modulate its binding to its cognate enhancer DNA.
Figure 5: The oligomeric state of HNF-4α is affected by long-chain fatty acyl-CoAs.

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Acknowledgements

We thank S. Malik for HNF-4 cloned into 6-HispET11d, S. Smith for pJLA502, F.Sladek for pLEN4S plasmids and Y. Shaul for AdML 200-G-less cassette plasmids. This work was supported by the Israel National Science Foundation.

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Correspondence to Jacob Bar-Tana.

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Hertz, R., Magenheim, J., Berman, I. et al. Fatty acyl-CoA thioesters are ligands of hepatic nuclear factor-4α. Nature 392, 512–516 (1998). https://doi.org/10.1038/33185

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